Review: Selective degradation of peroxisome by autophagy in plants: Mechanisms, functions, and perspectives

Accepted Manuscript Title: Review: Selective degradation of Peroxisome by autophagy in plants: mechanisms, functions, and perspectives Authors: Mengqian Luo, Xiaohong Zhuang PII: DOI: Reference:

S0168-9452(18)30434-5 https://doi.org/10.1016/j.plantsci.2018.06.026 PSL 9895

To appear in:

Plant Science

Received date: Revised date: Accepted date:

20-4-2018 28-6-2018 29-6-2018

Please cite this article as: Luo M, Zhuang X, Review: Selective degradation of Peroxisome by autophagy in plants: mechanisms, functions, and perspectives, Plant Science (2018), https://doi.org/10.1016/j.plantsci.2018.06.026 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Review: Selective degradation of Peroxisome by autophagy in plants: mechanisms, functions, and perspectives

for Cell & Developmental Biology, State Key Laboratory of

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1Centre

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Mengqian Luo1 and Xiaohong Zhuang1*

Agrobiotechnology, School of Life Sciences, The Chinese University of Hong

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Kong, Shatin, New Territories, Hong Kong, China

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*Corresponding author:

Highlights

Peroxisomes biogenesis involves divergent modes in various organisms

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

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Zhuang, X. ([email protected]).

with the conserved peroxisomal components. Pexophagy is crucial for maintenance of peroxisome homeostasis and

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

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remodeling of seedlings in plants.

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Core peroxins and ATG proteins essential for plant pexophagy have been identified in plant.

Abstract 1

Peroxisome, a single-membrane organelle conserved in eukaryotic, is responsible for a series of oxidative reactions with its specific enzymatic components. A counterbalance between peroxisome biogenesis and degradation is crucial for the homeostasis of peroxisomes. One such

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degradation mechanism, termed pexophagy, is a type of selective autophagic

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process to deliver the excess/damaged peroxisomes into the vacuole. In

plants, pexophagy is involved in the remodeling of seedlings and quality control of peroxisomes. Here, we describe the recent advance in plant

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pexophagy, with a focus to discuss the key regulators in plants in comparison

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with those in yeast and mammals, as well as future directions for pexophagy

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studies in plants.

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Keywords: ATG proteins, de novo peroxisome biogenesis, peroxins,

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pexophagy, pexophagy receptor, selective autophagy

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1. Introduction

Peroxisomes are small single-membrane bound organelles conserved in

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eukaryotic cells, which participate in various cellular processes, including lipid metabolism (e.g. β-oxidation) and reactive oxygen species conversion (e.g., hydrogen peroxide) [1-3]. In addition, peroxisomes regulate photorespiration

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and the synthesis of phytohormones, which are critical for signaling pathways, including the jasmonic acid, auxin, and salicylic acid [1-3]. Peroxisomes display amazing dynamic variations in shape and size, as well as motility, which are directly linked to the cell type, the developmental

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stage, and environmental stimuli. They can rapidly adapt to cellular demands

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with profound increasing size and number [4]. Hence, regulation of their biogenesis and degradation process is essential for peroxisome homeostasis in diverse cellular events. Genetic and proteomic studies have identified a set

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of proteins named peroxins (PEX) essential for peroxisome biogenesis, which

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are highly conserved among eukaryotes [5]. To date, more than 20 plant

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peroxin genes have been identified, while approximate 20 peroxin genes in mammals and at least 32 have implicated in yeast [6-8].

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Two models, including (1) growth and division from pre-existing peroxisome, and (2) de novo biogenesis from ER, are reported to contribute to

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peroxisome biogenesis [9, 10]. In the growth and division model, the

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peroxisomes are divided from the pre-existing peroxisomes, while the peroxisomal membrane proteins (PMPs) are directly targeted to peroxisomal

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membrane after translation on cytosolic ribosomes [14-16] (Figure 1d). In the de novo biogenesis model, the PMPs are inserted into the peroxisomal membrane by trafficking from the ER for the generation of the preperoxisomal vesicles and specialized lamellar ER extensions to contribute to the

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peroxisome formation

[10, 17] (Figure1a and 1b). In addition, mitochondria

have been implicated to function in peroxisome biogenesis in mammals [18] (Figure1b). In plants, clear evidence for de novo peroxisome biogenesis from the ER is still lacking, but an “ER semi-autonomous peroxisome maturation

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and replication” model has been proposed [19] (Figure1c). In particular, a

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unique peroxisome-to-ER retrograde pathway has been reported in plants upon the tomato bushy stunt virus infection [25] (Figure1c).

On the other hand, the excess or damaged peroxisomes are degraded

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via either protease-mediated or autophagy-mediated pathway [11, 12].

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Autophagy is an essential metabolic process, which requires the core

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autophagy-related (ATG) proteins to deliver the damaged/unwanted cellular contents into the vacuole/lysosome for degradation and recycling [13].

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Selective degradation of peroxisome by autophagy is termed as pexophagy, while increasing efforts have been put to characterize the underlying

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mechanism of pexophagy in both yeast and mammals. In recent years,

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pexophagy has been observed in plant cells as well. In this review, we attempt to discuss the recent progress in our understanding of peroxisome biogenesis

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and degradation in plants, with a focus on pexophagy in comparison with that in yeast and mammals. 2.Peroxisome degradation and pexophagy

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After formation and proliferation to involve in various metabolic processes or upon stress induction, excess, damaged, oxidized or misfolded peroxisomal proteins need to be degraded for the maintenance of peroxisome homeostasis. Two types of degradation pathways, mediated by protease enzymes and

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pexophagy respectively, have been reported for peroxisome degradation

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(Figure 2).

Protease-mediated degradation of peroxisome has been reported in both mammals and plants. In mammals, Lon protease and 15-lipoxygenase are

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involved in the degradation of peroxisomal enzymes and the peroxisomal

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membrane lipids through inducing the release of proteins from the organelle

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lumen respectively [27, 28] (Figure 2a and 2b). The LON protease has also been implicated in plant peroxisome degradation, while deficiency of the LON

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protease will result in abnormal enlarged peroxisomes [29, 30]. In addition, it has also been recently reported that E3 ubiquitin ligase SP1 [suppressor of

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plastid protein import locus 1 (ppi1) 1] is involved in the degradation of

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peroxisome biogenesis factors such as PEX13 [31]. SP1 promotes the PEX13 degradation, and plays a negative role in the peroxisome biogenesis [31].

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Interestingly, the negative effect of SP1 on the peroxisome biogenesis could be suppressed by the expression of SP1-Like 1 (SPL1) protein, a close homolog of SP1, suggesting that distinct mechanisms are utilized by the E3 ligase family for regulating peroxisome degradation [32].

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On the other hand, peroxisome can be selectively degraded via pexophagy. In Arabidopsis, accumulation of the environmental reactive oxygen species (ROS) may activate pexophagy, which targets the peroxisome aggregates for

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degradation to protect the cells from toxic damage [33]. It is also shown that

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pexophagy is essential for fungal pathogenesis in plant cells. For example,

when Colletotrichum orbiculare infects the plant cells, it will undergo peroxisome degradation in an ATG26-dependent manner [34, 35]. To date,

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two types of pexophagy have been characterized, including macropexophagy

2.1 Micropexophagy

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and micropexophagy [36].

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Micropexophagy is primaryly characterized in yeast. In Pichia pastoris, micropexophagy is induced when cells were transferred to glucose [37, 38].

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During micropexophagy, vacuolar membrane expands to sequester the

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peroxisomes into the specific arm-like structures named as vacuolar sequestering membrane [39]. These arm-like structures are separated into

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pieces to form the micropexophagic membrane apparatus (MIPA), which is required for the engulfment of peroxisomes. Subsequently, upon membrane fusion between the MIPA and the vacuolar membrane, the peroxisomes will be released into the vacuole lumen for degradation [39] (Figure 2a). Both Atg30

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and Atg37 are required for micropexophagy [40, 41]. In addition, two adaptor proteins, Atg11 and Atg17, are reported to function in the formation of the pexophagy-specific vacuolar sequestering membrane [41]. In Ppatg30Δ, Atg11 fails to traffic to the perivacuolar structures, and the formation of

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functional MIPA is blocked [41]. Different from Atg11, Atg17 coordinates with

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pexophagy-specific Atg28 and micropexophagy-specific Atg35 to promote the formation of the MIPA [42, 43]. However, micropexophagy in mammals and

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plants has not been reported yet [37].

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2.2 Macropexophagy

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Macropexophagy is featured by the formation of a double-membrane structure, named as autophagosome, for the sequestration of peroxisomal cargos, which

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has been observed in yeast, mammals and plants [44-46]. During macropexophagy, the peroxisomal cargos are recognized by the pexophagy

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receptor(s), which will recruit other core ATG machinery for the formation of

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pre-autophagosome structures (also known as phagophore assembly site). After elongation and expansion, the peroxisomal cargos are sealed into the

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autophagosome and delivered into the lysosome/vacuole for degradation and recycling [13]. In yeast, macropexophagy could be induced by low energy level and switched to micropexophagy under a high ATP level [47]. In mammals, pexophagy is related to the peroxisome biogenesis disorders, a disease which

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is defective in the formation of functional peroxisomes [48]. In Arabidopsis, pexophagy has been shown to involve in seedling remodeling and peroxisome quality control during plant development [2, 11, 46, 49]. Exciting progress has been achieved in recent years, revealing a critical role of pexophagy in plant

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cells, and several key regulators in this process have been identified.

2.2.1 Macropexophagy in seedling remodeling for plant development The β-oxidation and the glyoxylate cycle are essential for the conversion of

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lipids into carbohydrate during seed germination before the establishment of

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photosynthesis [1, 2]. Two peroxisomal enzymes, called isocitrate lyase and

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malate synthase, are required in the glyoxylate cycle [1]. It is found that these two enzymes are degraded by macropexophagy after the establishment of

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photosynthesis and synthesis of the photosynthetic enzymes in young seedlings [50]. Deficiency in autophagy will lead to the accumulation of

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isocitrate lyase and malate synthase as well as the peroxisomal marker. In

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addition, the peroxisome marker is detected in the vacuole in wild type plants and colocalizes with autophagy marker in the hypocotyls, which is not

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observed in the autophagic defective mutants [51, 52]. A direct evidence for the requirement of pexophagy in the turnover of

peroxisomes in plants has been obtained recently by a genetic suppressor screening [30]. It is shown that atg mutation can suppress lon2 defects in

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peroxisomal metabolism, matrix protein import, as well as peroxisome size and abundance [29, 30, 53, 54]. Pexophagy is promoted to degrade the peroxisomal enzymes when the LON2-dependent degradation is inhibited [30, 55]. Noticeably, in the autophagy-deficient mutants like atg5 and atg7,

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peroxisomes accumulate at the hypocotyl and the leaf regions of the seedlings

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but not in root cells, suggesting that the levels of pexophagy are various in different types of tissues during seedling growth [51, 52]. Particularly, it is often

observed that the abnormal peroxisome structures are surrounded with the

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autophagosomal membrane at the site of the aggregates [52]. Taken together,

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these observations indicate that pexophagy is required for the removal of

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tissue-specific manner.

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dysfunctional peroxisomes under normal seedling growth condition in a

2.2.2 Macropexophagy is triggered when peroxisomes are damaged

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Accompanied with the photosynthesis, plant cells will undergo unique

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photorespiration to produce H2O2 as a byproduct. Excess production of H2O2 is toxic for plant development and requires peroxisomal enzymes for the reactive

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oxygen species (ROS) detoxification, such as the catalase (CAT) to breakdown H2O2 [1, 3]. However, superfluous H2O2 will damage the peroxisomes and subsequently trigger macropexophagy [33, 56]. Both exogenous application of H2O2 and cat2 mutation cause peroxisome

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aggregates [33] (Figure 2c). It is noted that atg mutants are more hypersensitive to the oxidative conditions, implying that ATG proteins are involved in the oxidative stress response [57, 58]. Furthermore, genetic screening has demonstrated that disruption of ATG2, ATG18a, ATG7 or ATG5

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leads to the accumulation of highly oxidative peroxisome aggregates with

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increased levels of inactive catalase, probably representing damaged

peroxisomes [33, 51, 52]. In addition, it is often observed that autophagosome marker ATG8 proteins colocalize with the peroxisome aggregates in these atg

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mutants [33, 59].

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2.2.3 Macropexophagy receptors for pexophagy recognition The selective degradation via pexophagy requires specific adaptors as a

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bridge to connect the peroxisome and the autophagic structures, or to promote the interaction with specific receptors during macropexophagy. Different cargo

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receptors and regulators (including ATG and non-ATG proteins) are reported

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to function in pexophagy in different systems [60] (Figure 2 and Table1). In yeast, specific receptors are found for the assembly of the

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receptor-protein complex (RPC), named as PpAtg30 in Pichia pastoris and ScAtg36 in Saccharomyces cerevisiae respectively [41, 61]. PpAtg30 contains the Atg8-interacting motif for binding to ATG8, and directly interacts with Pex3 and Pex14 on the peroxisomal membrane for peroxisome targeting [41]. Pex3

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is required for the activation of PpAtg30 via phosphorylation, a prerequisite for the association of PpAtg30 with the ATG machinery and peroxisomal proteins. It is shown that in pex3 mutant, PpAtg30 fails to localize to the peroxisome [41, 62]. But under starvation condition, PpAtg30 will interact with another scaffold

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protein Atg17 for the peroxisome-specific phagophore formation [41]. In

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Saccharomyces cerevisiae, macropexophagy is mediated by the receptor ScAtg36, which interacts with Pex3 for peroxisome targeting [62]. Although PpAtg30 and ScAtg36 share little protein sequence homology, they both bind

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to ATG8 and Atg11 [62, 63] (Figure 2a).

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In mammals, both NBR1 and p62 have been implicated as pexophagy

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receptors for pexophagy (Figure 2b). Overexpression of these two receptors will induce pexophagy. As pexophagy receptors, both NBR1 and p62 contain

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the essential functional LC3(ATG8 homolog in mammals)-interacting region for the linkage of peroxisomes and autophagic structures [64]. Also, it seems that

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NBR1 serve as the main autophagy receptor in mammalian cells while p62

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involves in pexophagy in an NBR1-dependent manner, as pexophagy still occurs after depletion of p62 [64]. Upon pexophagy, the E3 ubiquitin ligase

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PEX2 will trigger the ubiquitination of two peroxisomal membrane proteins, PEX5 and PMP70, which subsequently recruit NBR1 or p62 to promote pexophagy [65, 66]. In addition, mammalian NBR1 and p62 are also involved in other types of autophagy, such as mitophagy and lysophagy [60].

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In Arabidopsis, a counterpart of pexophagy receptor has not been characterized yet, but a hybrid of mammalian p62 and NBR1 do exist in Arabidopsis, named AtNBR1 [11, 46], which interacts with ATG8 via the AIM motif [67]. Previous studies have shown that the AtNBR1 is required for plant

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autophagy, and is important in the heat, oxidative, salt stresses tolerance [58].

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Upon heat stress, the number of insoluble, ubiquitinated proteins accumulate

and the level of CAT protein increases in the atnbr1 mutant background [58, 68]. It is very likely that AtNBR1 may function as a potential pexophagy

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receptor in plant, but it is also possible that other plant-specific receptors are

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involved in pexophagy. A recent study has revealed that several peroxins

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contain conserved AIM motifs, including PEX1, PEX6 and PEX10 [69]. BiFC assay shows that both PEX6 and PEX10 interact with ATG8. It requires further

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efforts to explore whether these ATG8-interacting proteins play a role in plant pexophagy as pexophagy receptors and how they are coordinated during

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pexophagy.

2.2.4 Peroxins in macropexophagy regulation

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In recent years, increasing studies support the essential roles of PEX proteins in regulating both peroxisome biogenesis and pexophagy in yeast and mammals (Table 1).

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In mammals, it is implicated that both PEX5 and PEX3 could trigger pexophagy by self-ubiquitination, and unknown receptor(s) may involve for their recognition [65, 70]. Under amino acid starvation conditions, mTORC1 may upregulate the expression level of PEX2 to activate the NBR1-dependent

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pexophagy [66]. Subsequently, three peroxins, PEX2, PEX10 and PEX12

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coordinate the PEX5 ubiquitination [65, 71]. In addition, both mammalian PEX13 and PEX14, have also been implicated in pexophagy. Depletion of

PEX13 in neuroblastoma cells may trigger pexophagy [48], but it is also noted

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that PEX13 functions in other selective autophagy pathways such as

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mitophagy and virophagy in mammals [72]. Intriguingly, PEX14, a

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transmembrane protein anchored on the peroxisomal membrane, involves in macropexophagy via binding to LC3 under starvation conditions. Moreover,

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under the normal condition, PEX14 will form a complex with PEX5 to compete the interaction between PEX14 and LC3 [73]. In addition, PEX5 mediates

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autophagy and lysosomal gene expression through mTOR signaling and

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Transcription Factor EB (TFEB) activity [74]. However, in yeast, Pex14 plays a distinct role in pexophagy via interaction with Atg30 to serve as a peroxisomal

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translocon [75, 76]. In mammals, PEX1, PEX6 and PEX26 will form the AAA (ATPases associated with various cellular activities)-type ATPase complex (AAA-complex), which is required for the recycling of PEX5 on the peroxisomal membrane. Blocking the function of AAA-complex leads to the enhancement

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of PEX5 ubiquitination, which further triggers pexophagy [77]. Similar effect is also observed when the AAA-complex is disrupted in yeast [78]. In Arabidopsis, whether PEX3 or PEX5 is involved in pexophagy has not been investigated yet, but they both conversely function in peroxisome

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biogenesis, as well as other peroxins. PEX3 involves in the peroxisomal

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morphology determination and depletion of pex3 leads to tubular peroxisomes

structures [79]. PEX5 recognizes the signal from PTS1 and is required for maintaining the proper functions of PTS2 receptor named PEX7 [80, 81].

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PEX2 and PEX10 coordinate to promote peroxisomal protein import, including

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recycling of PEX5 [82]. Depletion of PEX10 is embryo lethal, with defects in

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peroxisome and other storage organelle (e.g. lipid droplet) formation during embryogenesis [83, 84]. The docking of PEX5 on the peroxisomal membrane

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requires PEX13, and the level of the membrane-associated PEX5 is decreased in the pex13 mutant [85]. In addition, protein import on the

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peroxisomal membrane requires both PEX13 and PEX14 in Arabidopsis [86,

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87]. Like mammals, PEX14 forms a complex with PEX5 in Arabidopsis [88]. Although the involvement of peroxin proteins in peroxisome biogenesis

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has been well established in plants, the underlying mechanisms of peroxins in plant pexophagy regulation are still poorly explored. Whether they participate in plant pexophagy as those in yeast or mammals, or a plant-specific mechanism is involved remains unclear. Recently, it is suggested that

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pexophagy was promoted in Arabidopsis pex1 mutant, as disruption of autophagy in pex1 eliminated the abundance of abnormal peroxisomes [91]. A negative role of PEX1 and PEX6 in pexophagy induction is further supported by another study in Arabidopsis [90]. It was observed that dysfunction of

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PEX1-PEX6 accelerated pexophagy, while blocking autophagy complemented

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the defects of pex6 mutant [90]. Interestingly, a pex1-1 allele has restored the defects in pex6, suggesting that PEX1 and PEX6 may play additional roles in Arabidopsis [90]. Further investigations on the mechanisms of peroxins in

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regulation mechanism in plant pexophagy.

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plant pexophagy will certainly help us to obtain a better understanding of the

2.2.5 ATG machinery in macropexophagy regulation

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Most of the core ATG components have been reported to involve in pexophagy in yeast, mammals as well as plants. It is reasonable that disruption of the

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general autophagy pathway also compromises the pexophagy. Here we will

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discuss several key ATG components during pexophagy, including Atg37 and

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Atg11.

Atg37,

an

integral

peroxisomal

membrane

protein,

has

been

demonstrated to specifically function during phagophore formation for pexophagy.

When

pexophagy

is

induced

in

Pichia

pastoris,

the

phosphorylated PpAtg30 will recruit Atg37, which subsequently binds to the

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scaffold protein Atg11 to facilitate autophagosome formation [40]. The mammalian homolog of yeast Atg37, acyl-CoA–binding domain containing protein 5 (ACBD5), is also shown to be required specifically for pexophagy as well as peroxisome biogenesis. It has been previously reported that

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knockdown of ACBD5 impaired the peroxisomal β-oxidation [92]. ACBD5

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binds to an ER protein vesicle-associated membrane protein-associated

protein B (VAPB), which plays a role as a primary ER–peroxisome tethering factor to regulate the connection between ER and peroxisomes [40, 93, 94]. In

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another study, it is observed that knockdown of ACBD5 may increase the

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peroxisome abundance in mammalian cells, suggesting that ACBD5 functions

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as a positive regulator during pexophagy similar to the yeast Atg37 [40]. In Arabidopsis, acyl-CoA-binding proteins (ACBPs) are encoded by a family of

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six genes (ACBP1 to ACBP6), which are essential for diverse cellular activities [95]. Intriguingly, it is worth noting that overexpression of ACBP3 suppressed

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autophagy [96]. In contrast, overexpression of Atg37 does not interfere with

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pexophagy while overexpression of ACBD5 increases peroxisome–ER interactions [40, 94]. Whether ACBP3 or other ACBPs in Arabidopsis play a

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similar or distinct roles in pexophagy or peroxisome biogenesis needs further investigations. In yeast, Atg11 is another pexophagy-related ATG component, which has also been implicated in mitophagy and Cvt pathway, while another scaffold

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protein Atg17 is also required in the pexophagy under starvation condition [62, 97, 98]. As an adaptor protein, Atg11 binds to the cargo receptors at the specific pre-autophagosome structures to promote phagophore expansion [62]. In addition, it has been speculated that Atg11 might involve in both peroxisome

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recognition and autophagosome cargoes transportation along actin cables to

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the pre-autophagosome structures in Saccharomyces cerevisiae [99, 100]. In fact, a hybrid orthologue of ATG11 and ATG17 named AtATG11 in Arabidopsis has been identified to play roles in mitophagy and bulk autophagy

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[101]. It will be interesting to examine whether AtATG11 also functions in plant

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pexophagy.

2.2.6 Other regulators in plant macropexophagy

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In addition to the peroxins and core ATG machinery, other regulators have been identified to function in pexophagy. In a recent study, it is shown that

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Arabidopsis LON2 might function as a chaperone to mediate pexophagy [55].

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Previous researches mainly indicated that LON2 sustains the matrix protein import and degrades the peroxisomes through protease degradation as the

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mammalian LON protease [29, 55] (Figure 2c). In yeast, Lon protease Pln contributes to the degradation of soluble non-assembled peroxisomal proteins and pexophagy. In the pln mutant, the number of peroxisomes is increased with higher levels of ROS [102]. The viability of the cells is not affected in pln

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mutant when comparing with atg1, however, in the pln atg1 double mutant, the viability of the cells is greatly reduced than that of atg1, implying that Pln may negatively regulate macropexophagy in yeast [102]. But in the Arabidopsis lon2 mutant, larger abnormal peroxisomal structures are observed. Moreover,

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autophagy deficiency recovered the defects of abnormal large size

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peroxisomes in lon2, as several atg mutants may suppress the lon2 phenotype [30].

The integral membrane protein PMP34, which functions as an ATP

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transporter to provide ATP for the activation of fatty acids, is also implicated in

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pexophagy regulation [103]. In mammalian cells, it is observed that

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ubiquitination of PMP34 may enhance pexophagy [104]. However, deficiency of PMP47, the counterpart of mammalian PMP34 in yeast, does not interfere

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with pexophagy [105]. In Arabidopsis, devoid of PMP38 (homologue of PMP47) leads to a defect in peroxisome proliferation with enlarged peroxisomes and

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[106].

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reduced number, but whether it plays a role in plant pexophagy is unknown

During pexophagy, protein kinases have also been uncovered in

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mediating the signaling pathways. For example, Hrr25, a homolog of casein kinase 1δ, participates in PpAtg30 phosphorylation to negatively and positively regulate its binding to Pex3 and Atg37 respectively [107]. In S. cerevisiae, Hrr25 kinase is identified to function in ScAtg36 phosphorylation at its Atg11

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binding site for pexophagy activation [108]. Recently, a mitogen-activated protein kinase (MAPK) named Slt2p has also been demonstrated to function in pexophagy [101]. In mammals, it is also reported that Ataxia-telangiectasia mutated (ATM) kinase functions at the early step to phosphorylate PEX5 upon

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ROS activation, which in turn promotes PEX5 ubiquitination and its recognition

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by the pexophagy receptor p62 to initiate pexophagy [60]. However, future

studies are required to elucidate whether plant-specific signaling pathway is

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3. Conclusion and future perspectives

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involved in plant cells for pexophagy regulation.

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As the sole organelle for β-oxidation and major scavenger of hydrogen peroxide in plants, peroxisome plays crucial roles in plant growth and

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development. Although key components for peroxisome biogenesis are conserved in plants, the underlying mechanisms remain to be further

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elucidated. In the peroxisome degradation, pexophagy is important in

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maintaining the homeostasis of peroxisomes, controlling the peroxisome quality and promoting the remodeling of the seedlings. Although pexophagy

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has been demonstrated to occur in plant cells, how peroxisome is recognized and targeted into the vacuole by the autophagy machinery is still poorly understood. Several important questions remain to be answered: (1) How do the

autophagic

machinery

recognize

and

orchestrate

the

damaged

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peroxisome degradation? (2) Compared with yeast and mammals, do plants employ specific receptor(s) in pexophagy for peroxisome targeting in different species? (3) Does micropexophagy occur in plant cells? (4) How is the signaling pathway transduced for pexophagy activation? In order to answer

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these questions, identification of the plant pexophagy receptor(s) and the

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interaction network will be an extremely important task for plant pexophagy study in future.

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Acknowledgements

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We apologize to researchers whose work has not been included in this

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manuscript owing to space limit. This work was supported by grants from the Research Grants Council of Hong Kong (G-CUHK402/15, G-CUHK403/17,

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CUHK14130716, CUHK14102417, C4011-14R, C4012-16E, C4002-17G and AoE/M-05/12), the National Natural Science Foundation of China (31470294

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and 31670179).

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Figure legends Figure 1. The models for peroxisome biogenesis in yeast, mammals and plants. (a) In yeast, the peroxisomal RING proteins and docking subcomplex are

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transported into distinct small preperixosomal vesicles. Upon the fusion of the

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two sorting vesicles and recruitment of the PMPs, the new peroxisome could

be formed; (b) In mammals, the ER extends to form tubular-like larmellar pER extension followed with the protein import, which gives rise to the nascent

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peroxisomes. Mitochondria have also been implicated as a membrane source

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together with the ER to contribute to peroxisome formation and the

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hybrid-origin peroxisomes are gradually formed through vesicle fusion; (c) In plants, direct evidence for ER-derived pre-peroxisomal vesicles is lacking. But

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a compartment called ER-peroxisome intermediate compartment is suggested to act as an intermediate to fuse with the preexisting peroxisomes. In addition,

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a unique peroxisome-to-ER retrograde pathway occurs in plant cells upon

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tomato bushy stunt virus infection. During the retrograde process, the PMPs are transported back to ER via an unknown mechanism. (d) Growth and

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division model for peroxisome biogenesis in yeast, mammals and plants, in which the peroxisomes may elongate and proliferate by the fission process to produce the new daughter peroxisomes.

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Figure 2. Peroxisome degradation in yeast, mammals and plants. (a) Selective degradation of peroxisome via pexophagy in yeast. In micropexophagy, micropexophagy-specific membrane apparatus (MIPA) targets the peroxisomal cargoes and regulates fusion among the tips of the

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vacuole pieces. Subsequently, the peroxisomal matrix proteins are released

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into the vacuole for degradation. In macropexophagy, two pexophagy receptors, named PpAtg30 and ScAtg36, have been identified in two distinct

yeast species. Both PpAtg30 and ScAtg36 interact with peroxisomal protein and

autophagosomal

protein

Atg8.

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of

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autophagosome, peroxisomes will be delivered into the vacuole for

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degradation. (b) In mammalian cells, peroxisome degradation is mediated by macropexophagy, or autolysis by 15-lipoxygenase and protease-like LON

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protein respectively. During macropexophagy, NBR1 and p62 serve as the pexophagy receptors for interaction with PEX5 and LC3 to promote pexophagy.

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(c) In Arabidopsis, LON2- and macropexophagy- mediated peroxisome

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degradation pathways have been reported. Excess H2O2 or depletion of CAT leads to accumulation of peroxisome aggregates, which will be targeted by

A

macropexophagy for degradation. However, plant pexophagy receptor has not been identified yet.

31

32

EP

CC

A TE D

IP T

SC R

U

N

A

M

Table 1. Summary of the key ATG proteins, peroxisomal proteins and pexophagy receptors involved in macropexophagy. Mammals

Atg8

LC3A-C/GA BARAP /GABARAP L1-3 FIP200

ATG proteins Atg11

Arabidops is ATG8a-AT G8f

Molecular event in Arabidopsis Marker of autophagosomes

ATG11

Link ATG1-ATG13 complex as a scaffold

[113]

Involves in pexophagy, responses to oxidative stress Pexophagy, early senescence ACBP3 suppresses autophagy Peroxisomal morphology determination Receptor for PTS1 proteins Import matrix proteins into plant peroxisomes Import matrix proteins into plant peroxisomes, plant embryogenesis Docking protein, function in protein import Docking protein, function in protein import Pexophagy, recycle PEX5 and stabilize PEX6 Pexophagy, recycle PEX5 and utilize oil body PEX5 recycling guidance and oil body utilization ATP import to peroxisomes

[47]

Pexophagy, chaperone function and protease Xenophagy, stress responses

[43,44, 69]

Atg17 ATG18a-h

Atg2

ATG2

Atg37

ATG2a ATG2b ACBD5

Pex3

PEX3

Pex5 Pex2

PEX5 PEX2

PEX3-1 PEX3-2 PEX5 PEX2

Pex1 0

PEX10

PEX10

Pex1 4 Pex1 3 Pex1

PEX14

PEX14

PEX1

PEX1

Pex6

PEX6

PEX6

Pex1 5 PMP4 7 Pln

PEX26

PEX26

PMP34

PMP38

LON

LON2

Atg30 Atg36 Nbr1

NBR1, p62

NBR1

EP

N

A

PEX13

[47] [107,108] [32] [93,94] [95] [95-97]

[99,101] [100] [70,102] [102,103] [102] [118]

[73, 82]

A

CC

Pexophagy Receptors

U

ACBPs

M

PEX13

SC R

WIPI1-4

TE D

Peroxisom al Regulators

Atg18

Reference s [47,74]

IP T

Yeast

33