ADP-heptose: A new innate immune modulator

Accepted Manuscript ADP-heptose: A new innate immune modulator Xinyuan Hu, Chunhua Yang, Peng George Wang, Gao-Lan Zhang PII:

S0008-6215(18)30646-3

DOI:

https://doi.org/10.1016/j.carres.2018.12.011

Reference:

CAR 7652

To appear in:

Carbohydrate Research

Received Date: 1 November 2018 Revised Date:

18 December 2018

Accepted Date: 18 December 2018

Please cite this article as: X. Hu, C. Yang, P.G. Wang, G.-L. Zhang, ADP-heptose: A new innate immune modulator, Carbohydrate Research (2019), doi: https://doi.org/10.1016/j.carres.2018.12.011. 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.

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Graphical abstract Bacterial cell GmhB

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HldE/HldD

ADP

Kdo

Hep

GlcN

Directly

GlcN

LPS

Outer membrane

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the innate immune response

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ADP-Heptose: A new innate immune modulator Xinyuan Hua, Chunhua Yangb, Peng George Wangc, Gao-Lan Zhangc* The State Key Laboratory of Microbial Technology and National Glycoengineering Research Center,

Shandong University, Qingdao, 266237, China

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a

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Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia 30303, United States

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Department of Chemistry, Georgia State University, Atlanta, Georgia 30303, United States

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*To whom correspondence should be addressed: [email protected]

Abstract: Lipopolysaccharide (LPS) is a well-known pathogen-associated molecular pattern

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(PAMP) produced by gram-negative bacteria. Previous studies showed that a key metabolic intermediate in LPS biosynthesis, D-glycero-β-D-manno-heptose 1,7-bisphosphate (HBP), could activate the NF-κB pathway and trigger the innate immune responses. However, it was unclear whether HBP could be a novel PAMP and its pattern recognition receptor (PRR) is not fully understood. Very recently, the Shao group reported that another key metabolic intermediate in LPS biosynthesis, ADP-heptose, could be transported into mammalian cells and bind with

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ALPK1 (alpha-kinase 1), which leads to a series of strong immune responses. These findings broaden our understanding on bacterial metabolites as a new type of PAMP and these small molecules hold great potential to be applied in the development of novel immune modulators.

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This minireview focuses on the roles of ADP-heptose related metabolites in innate immunity.

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Keywords: ADP-heptose; biosynthesis; innate immunity; LPS; modulator

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A. A surprise discovery Innate immunity is known to be the first line of host defense during microbial infection and plays a critical role in the recognition and subsequent induction of the inflammasome response to

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invading pathogens. Upon infection, recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs) results in the activation of signal transduction pathways and the generation of a broad range of immune effectors including cytokines, chemokines and cell adhesion molecules[1-3]. At the same time, the innate immune response is

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intimately connected to the adaptive immune response and involved in the activation and shaping of the adaptive immunity[4].

A variety of PRR families have been discovered to date, including Toll-like receptors (TLRs),

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nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), retinoid acidinducible gene I (RIG-I)-like receptors (RLRs) and C-type lectin receptors (CLRs)[5]. On the other hand, many biomolecules have been disclosed to act as PAMPs, such as lipopolysaccharide (LPS), peptidoglycan, glycolipids and CpG oligodeoxynucleotide (Figure 1). To maintain immune homeostasis, PAMPs are usually evolutionarily conserved structures from pathogens and could be found in many pathogenic microorganisms. PAMPs act as “pathogen barcode” that

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could inform the host of infectious risks brought by a microorganism[6]. Identification of new PAMPs could help us understand the pathogenic invasion process and develop novel strategies to combat bacterial infections and auto-immune diseases.

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A recent article published in Nature by the Shao group showed that ADP-β-D-manno-heptose (ADP-heptose), a small molecular intermediate in the biosynthetic pathway of LPS, is a potent PAMP and ALPK1 (alpha-kinase 1) is its specific PRR (Figure 1)[7]. This finding greatly

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broadens our understanding of the types of PAMPs and adds to a growing awareness that bacterial metabolites can also act as PAMPs. Herein, this review focuses on the roles of ADPheptose in innate immune responses by introducing the brief history of ADP-heptose, its biosynthesis, the recent discoveries of the roles of ADP-heptose in innate immunity, as well as biological insights into the role of ADP-heptose.

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Figure 1. Activation of innate response through the interaction between PAMPs and PRRs. Note: not all types of PAMPs and PRRs are shown.

B. A brief history of ADP-heptose

Lipopolysaccharide (LPS), an essential component of the outer membrane of gram-negative

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bacteria, forms an effective barrier against various environmental stresses and plays a crucial role in pathogenesis[8]. It is typically comprised of three regions: lipid A (known as endotoxin),

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core region and O-antigen (known as O-polysaccharide). The core region can be further divided into the inner core and the outer core[9]. The inner core is highly conserved across serotypes of one bacterial species, and majority of innter cores from various bacteria contain 3-deoxy-Dmanno-oct-2-ulosonic acid (Kdo) and L-glycero-D-manno-heptopyranose (L,D-heptose) units which can be substituted by phosphate (P), pyrophosphate (PP) or diphosphoethanolamine (PPEtN) (Figure 2)[10]. L,D-Heptose

is prevalent in the LPS inner core of gram-negative bacteria, whereas D,D-

heptose is a common component of the outer core of LPS. Many bacteria, such as Haemophilus ducreyi, Klebsiella pneumonia, and Helicobacter pylori contain L,D-heptose in the inner core and 3

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D,D-heptose

in the outer core[11-13]. In addition, D,D-heptose is described as a constituent of S-

layer glycoproteins, the monomolecular crystalline proteins which are present on the cell surface of many archaea and bacteria[14, 15]. In the early 1980s, ADP-D,D-heptose and ADP-L,D-heptose were isolated from Shigella

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sonnei[16] and Salmonella minnesota[17], and identified as precursors for heptose residues in the LPS biosynthesis. Using synthetic substrates, in vitro biochemical assays revealed that the heptosyltransferases WaaC and WaaF from Escherichia coli prefer ADP-L,D-heptose as their substrate, while ADP-D,D-heptose can only be utilized at low efficiencies[18-21]. Other than as a

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key intermediate of the biosynthetic pathway of LPS of gram-negative bacteria, ADP-heptose was also found to be involved in the biosynthesis of certain secondary metabolites of gram-

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positive bacteria, such as septacidin and hygromycin B[22].

Figure 2. Schematic representation of the chemical structure of LPS in some gram-negative bacteria.

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Abbreviations: GlcN, glucosamine; Kdo, 3-deoxy-D-manno-oct-2-ulosonic acid; Hep, L-glycero-Dmanno-heptose; P, phosphate; EtN, ethanolamine; zig-zag lines, fatty acids.

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C. Biosynthesis of ADP-heptose The biosynthesis of nucleotide-activated heptose precursors has been studied genetically and biochemically, and the pathway is well conserved among gram-negative bacteria. These nucleotide-activated heptoses mainly include ADP-D, D-heptose, ADP-L, D-heptose and a less common GDP-D, D-heptose[23]. Generally, ADP-L, D-heptose is generated followed by a six-step biosynthetic pathway (Scheme 1): i) the formation of sedoheptulose 7-phosphate (S-7-P) by coupling of ribose-5phosphate and xylulose-5-phosphate under the catalysis of transketolase (TktA); ii) conversion of S-7-P to D-glycero-D-manno-heptose 7-phosphate catalyzed by the keto-aldose isomerase 4

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GmhA;

iii)

the

anomeric

phosphorylation

catalyzed

by

the

bifunctional

kinase/adenylyltransferase HldE[24] forming D-glycero-β-D-manno-heptose 1,7-bisphosphate (HBP); iv) dephosphorylation at the C-7 of HBP by the phosphatase GmhB; v) adenylylation of the D-glycero-D-manno-β-heptose 1-phosphate under the catalysis of HldE to form ADP-D,D-

L,D-heptose[25-28].

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heptose; and vi) epimerization at C-6 position catazlyed by the epimerase HldD affording ADPIn Neisseria meningitidis, the bifunctional enzyme HldE is replaced by two

individual enzymes: HldA and HldC. HldA functions as the β-D-heptose-7-phosphate kinase and HldC functions as the β-D-heptose-1-phosphate adenyltranferase[29, 30]. The resulting activated

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heptose unit can then be integrated by heptosyltransferases (WaaC, WaaF and WaaQ if a third heptose molecule is present) into the core region of LPS[31].

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Very recently, the Chen group discovered that septacidin, a secondary metabolite from a gram-positive bacterium, shares the same ADP-heptose biosynthesis pathway with the gramnegative bacterial LPS[32]. Enzymes involved in the synthesis of septacidin heptose are bracketed and indicated in green in Scheme 1. The S-7-P was transformed to ADP-D,D-heptose by SepB and SepL. SepC is the C-6 position epimerase converting ADP-D,D-heptose to ADPL,D-heptose.

For the biosynthesis of hygromycin B , the authors found that the isomerase HygP

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could convert S-7-P to D-glycero-D-altro-heptose 7-phosphate through consecutive isomerization, which is quite uncommon for sugar isomerases. Moreover, GmhB and HldE can tolerate the Dglycero-D-altro-heptose 7-phosphate stereochemistry and produce ADP-D-glycero-β-D-altro-

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in Scheme 3.

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heptose successfully (Scheme 2). The proposed biosynthetic pathway of hygromycin B is shown

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Scheme 1. The biosynthetic pathway for ADP-D,D-heptose and ADP-L,D-heptose involved in LPS generation. The enzymes involved in the biosynthesis of septacidin are bracketed and highlighted in green.

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Scheme 2. The biosynthetic pathway of ADP-D-glycero-β-D-altro-heptose in hygromycin B generation.

Scheme 3. The proposed biosynthetic pathway for hygromycin B.

GDP-D, D-heptose has been found in bakers’ yeast[33, 34] and has also been identified as the donor substrate of glycosyltransferases involved in the assembly of glycans on S-layer glycoproteins of Aneurinibacillus thermoaerophilus[35, 36]. Furthermore, the 6-deoxy heptose 6

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presented in capsules of many bacteria such as Yersinia pseudotuberculosis and Campylobacter jejuni is also derived from the GDP-D-α-D-heptose pathway[35, 37-40].

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D. Recent discovery of the roles of ADP-heptose in the innate immunity The family of Toll-like receptors (TLRs) is a major class of PRRs and has been extensively studied. LPS is specifically recognized by TLR4 and is a strong activator of NF-κB and inflammasome pathways[41]. Recent achievements in cell biology showed that host cells can

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detect and respond to HBP, a highly conserved metabolic intermediate in LPS biosynthesis. Similar to LPS, HBP could also activate the NF-κB pathway and the innate immune responses[29, 42]. Sensing of HBP triggers the activation of TIFA (TRAF-interacting protein

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with forkhead-associated domain)-dependent pathway (Figure 3). In addition, ALPK1, an upstream kinase of the TIFA-dependent pathway, was reported to be a master regulator of HBPinduced innate immunity[43]. Very recently, the Sauvageau group found that D-glycero-β-Dmanno-heptose 1-phosphate (β-HMP) could also induce TIFA-dependent NF-κB signaling and inflammatory response in a similar way with β-HBP[44]. However, it was unclear whether HBP

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is a true PAMP and the corresponding PRR was not confirmed.

The Shao group reported that when ADP-heptose was added directly to host cells, NF-κB signaling pathway could be activated through the ALPK1-TIFA-TRAF6 axis[7] (Figure 3). In addition, ADP-heptose could bind ALPK1 with a 100-fold higher affinity than HBP. The authors

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proposed that binding ADP-heptose to ALPK1 may trigger conformational changes and stimulate its kinase domain to phosphorylate and further activate TIFA, which eventually led to

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activation of the downstream NF-κB pathway. Importantly, they also found that HBP can not act directly as a PAMP, instead, it was converted by host adenylyltransferases into ADP-heptose 7-P and the latter activates ALPK1 with a lesser extent than ADP-heptose (Figure 3). Moreover, robust inflammatory responses were generated when mice were injected with ADP-heptose, while HBP injection has no detectable effect on the production of the inflammatory mediators. Therefore, it was identified that ADP-heptose, but not HBP, is a novel PAMP, and ALPK1 is its specific cytosolic PRR. Recognition of ADP-heptose by ALPK1 is a new form of innate sensing which mediates immune responses to invasion by various pathogens. Since ADP-heptose can

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directly enter mammalian cells, it could be a promising target to develop immunomodulators or

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vaccine adjuvants.

Figure 3. LPS metabolic intermediates trigger the host immune responses.

E. More biological insights into the roles of ADP-heptose

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Heptose is mostly restricted to the bacterial kingdom, which has not yet observed in mammalian cells. Blockade of heptose biosynthesis results in the increased bacterial sensitivity

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to antibiotics and reduction of virulence[45]. The abundance of LPS ensures the ADP-heptose biosynthetic pathway is highly active during bacterial growth and proliferation. Therefore, inhibition of ADP-heptose biosynthesis is regarded as an attractive approach for the design of novel antibiotics.

Citrobacter rodentium, a human attaching-effacing enteropathogen used in the mouse model[46], initiates infections by adhering to intestinal epithelial cells. This adhesion is mediated by the autotransporter [47]. Interestingly, recent research showed that before crossing the bacterial inner membrane, the autotransporter would be heptosylated on numerous serine residues by the cognate bacterial autotransporter heptosyltransferase (BAHT)[48] [49](Figure 4A). This 8

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modification is critically required for the bacterial colonization on the gastrointestinal tract of mice. The function of ADP-heptose as the donor of BAHT to heptosylate the autotransporter may provide new avenues for the development of novel therapeutics and vaccines against enteropathogen infections.

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ALPK1 has been identified as a susceptible gene of colitis in mice models and it can promote intestinal homeostasis by regulating the balance of Th1/Th17 immunity in response to microbial challenges[50]. Previous studies showed that during the infection of gastrointestinal pathogens, the release of HBP inside the host cells would activate the ALPK1- and TIFA-dependent innate

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immune pathway and then trigger NF-κB mediated inflammatory response (Figure 4B)[51, 52]. Based on recent study from the Shao group[7], it is proposed that ADP-heptose, like HBP, may

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also participate in the host cellular immune response during the infection of enteropathogens to gastrointestinal epithelial cells. A.

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BAHT

Adhesion and colonization

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B.

HBP BAHT Autotransporter

ALPK1

Cytokines

P

TIFA

TRAF6

e.g. IL-8 P

TAK1

NF-κB Proinflammatory genes

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Figure 4. A) The adhesion and colonization process followed by heptosylation of the autotransporter; B) The immune response triggered by the release of ADP-heptose and HBP in the gastrointestinal epithelial cell.

F. Perspectives

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The rapid and robust initiation of innate immune response is critical for host cells against microbial infections. For this defense, early recognition of PAMPs from invading pathogens by PRRs in host cells is paramount, and many mechanisms are involved for sensing pathogen invasion. Discovery of new PAMPs and PRRs advances our understanding on how host cells

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distinguish between self and non-self. In recent years, there are increasing reports concerning bacterial metabolites (such as HBP and analogs) that could be recognized by host cells. The work

recognized by novel PRRs[53].

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of the Shao group highlighted this concept: bacterial metabolites can act as PAMPs to be

Investigation on the invasion and defense process mediated by ADP-heptose and ALPK1 may contribute to develop new therapeutics in combating bacterial infections. However, many questions remain unanswered concerning the newly identifed PAMP, ADP-heptose. For example, how does the pathogenic microbial ADP-heptose enter the cytoplasm of the host cell? The Shao

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lab mentioned that for Y. pseudotuberculosis, this process requires the type III secretion system (T3SS), although the interaction of T3SS with ADP-heptose is unclear. Besides, the Meyer lab found that ADP-heptose in H. pylori triggered the NF-κB activation in a type IV secretion system (T4SS)-dependent manner[54]. However, for bacteria such as Shigella

flexneri,

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Salmonella typhimurium and Pseudomonas aeruginosa, they utilize T3SS apparatus to evade the host cells[55, 56]. So does ADP-heptose in these bacteria enter the target cells via T3SS or

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another unknown transport system? In addition, how can host cells avoid responses to ADPheptose produced by commensal bacteria? Moreover, since the ALPK1-TIFA signaling pathway has only been identified in certain cells so far, it is unclear whether it is a major PRR existing in all types of cells[57].

Further studies on ALPK1-ADP-heptose axis would also help to understand the homeostatic interplays between the gut microbiota and the intestinal innate immunity, based on which novel therapeutic opportunities for precision medicine might be developed for the treatment of inflammatory bowel diseases (IBD) and other autoimmune inflammatory diseases.

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Acknowledgement We would like to acknowledge the National Institutes of Health (U01GM116263) for financial support of this work.

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Highlights: 1. The recent research on the biosynthesis of ADP-heptose is reviewed;

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2. The discovery of ADP-heptose as a novel pathogen-associated molecular pattern (PAMP) is reviewed;

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3. The new roles of ADP-heptose in enteropathogen infection are reviewed.