- Email: [email protected]
Proteostasis or Aging: Let the CHIPs Fall Where They May
Developmental Cell
Previews more hypoxic (Jain, 2014). This highlights the need for appropriate and personalized dosing. The blood vessel normalization signature described by Tian and colleagues may help in identifying patients that will benefit from combination therapies. Finally, a major outstanding question relates to the molecular mechanism through which T lymphocytes promote blood vessel normalization. While the authors provide interesting clues relating to chemokine-induced attraction of pericytes that stabilize blood vessels, much of these findings remain correlative. Also, the differential effects that CD4+ and CD8+ T cells exert on the tumor vasculature and metastatic propensity are interesting topics for further analyses. This exciting and elegant study by Tian and colleagues
(2017) therefore opens the window to more detailed molecular and mechanistic studies of the signaling pathways that determine T lymphocyte-induced blood vessel normalization. Such complementary studies could reveal additional therapeutic targets that can be leveraged to achieve a better perfusion, as well as an enhanced immune response in tumors. REFERENCES
Huang, Y., Goel, S., Duda, D.G., Fukumura, D., and Jain, R.K. (2013). Cancer Res. 73, 2943–2948. Hugo, W., Zaretsky, J.M., Sun, L., Song, C., Moreno, B.H., Hu-Lieskovan, S., Berent-Maoz, B., Pang, J., Chmielowski, B., Cherry, G., et al. (2016). Cell 165, 35–44. Jain, R.K. (2014). Cancer Cell 26, 605–622. Keith, B., Johnson, R.S., and Simon, M.C. (2011). Nat. Rev. Cancer 12, 9–22. Thienpont, B., Steinbacher, J., Zhao, H., D’Anna, F., Kuchnio, A., Ploumakis, A., Ghesquie`re, B., Van Dyck, L., Boeckx, B., Schoonjans, L., et al. (2016). Nature 537, 63–68.
Carmeliet, P., and Jain, R.K. (2011). Nature 473, 298–307.
Tian, L., Goldstein, A., Wang, H., Lo, H.C., Kim, I.S., Welte, T., Sheng, K., Dobrolecki, L.E., Zhang, X., Putluri, N., et al. (2017). Nature. Published online April 3, 2017. http://dx.doi.org/10.1038/ nature21724.
Casazza, A., Di Conza, G., Wenes, M., Finisguerra, V., Deschoemaeker, S., and Mazzone, M. (2014). Oncogene 33, 1743–1754.
Wallin, J.J., Bendell, J.C., Funke, R., Sznol, M., Korski, K., Jones, S., Hernandez, G., Mier, J., He, X., Hodi, F.S., et al. (2016). Nat. Commun. 7, 12624.
Blank, C.U., Haanen, J.B., Ribas, A., and Schumacher, T.N. (2016). Science 352, 658–660.
Proteostasis or Aging: Let the CHIPs Fall Where They May Robyn Branicky1 and Siegfried Hekimi1,* 1Department of Biology, McGill University, Montreal H3A 1B1, Canada *Correspondence: [email protected] http://dx.doi.org/10.1016/j.devcel.2017.04.006
The conserved E3 ubiquitin ligase CHIP/CHN-1 contributes to proteostasis by ubiquitylating HSP70 and HSP90-interacting proteins. In a recent issue of Cell, Tawo et al. (2017) show that CHIP/CHN-1 also directly ubiquitylates the insulin receptor INSR/DAF-2 to regulate its turnover. These findings suggest an unexpected interpretation of the effects of altered proteostasis on survival. Proteostasis is maintained by an extensive quality-control network that promotes correct protein folding and degrades misfolded and aggregated proteins. It has long been observed that aging is associated with a decline in proteostasis, whereas enhanced proteostasis might be capable of increasing survival (Vilchez et al., 2014). However, it is not clear whether protein misfolding is causal to aging and, if so, whether the effect is due to the toxicity of the aberrant proteins or aggregates. A recent paper in Cell from Tawo et al. (2017) sheds light on this question. Changes in the activity of the conserved insulin/IGF-1 signaling pathway (IIS) are well known to affect the aging pro-
cess in a variety of organisms. Tawo et al. (2017) show that CHN-1, a conserved E3 ubiquitin ligase, directly ubiquitylates the insulin receptor DAF-2 in C. elegans. They also find that upon proteotoxic stress, the levels of DAF-2 are increased. This results in an upregulation of IIS signaling, which shortens lifespan. They suggest that under proteotoxic stress CHN-1 is redirected from DAF-2 to misfolded proteins, thus preventing ubiquitylation of DAF-2 and limiting lifespan. Importantly, this phenomenon appears to be conserved. Indeed, both the Drosophila (dCHIP) and human (CHIP) ligases ubiquitylate the insulin receptors (dINSR and INSR, respectively), and in both systems, proteotoxic stress
126 Developmental Cell 41, April 24, 2017 ª 2017 Elsevier Inc.
leads to increased levels of receptor protein. These findings suggest a mechanism for how protein aggregation might limit lifespan, one not based principally on the toxicity of misfolded proteins or protein aggregates. Initial observations by Tawo et al. (2017) suggested that chn-1, which encodes the C. elegans ortholog of CHIP, interacts genetically with the IIS signaling pathway. Activation of the IGF-1/INSR receptor (DAF-2 in C. elegans) activates a conserved PI3-kinase/AKT signaling cascade that phosphorylates FOXO transcription factors, preventing their accumulation in the nucleus. Reducing IIS signaling allows FOXO to accumulate in the nucleus and
Developmental Cell
Previews activate the transcription of chaperones HSP70 and No CHN-1 genes that promote longevity. HSP90 and promoting the or Low DAF-2 loss of DAF-2 Ub site Wild type Tawo et al. (2017) find that ubiquitylation and proteasomal or levels loss of C. elegans chn-1 indegradation of the proteins to proteotoxic stress creases IIS signaling: in chn-1 which they bind (Connell mutants, nuclear localization et al., 2001). Consistent with Ub Ub Ub DAF-2/INSR DAF-2/INSR DAF-2/INSR of the FOXO transcription CHN-1 also having this funcfactor DAF-16 is reduced, as tion, Tawo et al. (2017) find is transcription of its target that C. elegans chn-1 mutants genes. Accordingly, chn-1 are sensitive to heat stress, DAF-16/FOXO DAF-16/FOXO DAF-16/FOXO mutants have a reduced lifeoxidative stress, and the presspan. Indeed, further genetic ence of aggregation-prone analysis confirms the idea proteins, all of which are known Normal Increased Decreased that chn-1 acts via daf-16: the to be proteotoxic. A key finding Lifespan Lifespan Lifespan authors found that the reduced of the paper, which links these lifespan in chn-1 mutants is not functions, is that in the presFigure 1. Regulation of Lifespan via Ubiquitylaton of the Insulin enhanced by loss of daf-16 ence of CHN-1 all these Receptor and can be overcome by overstressors result in elevated The authors identify a conserved role for the E3 ubiquitin ligase CHIP/dCHIP/ CHN-1 in ubiquitylating the insulin receptor: DAF-2 in C. elegans, dINSR in expression of the DAF-16 proDAF-2 levels, suggesting that Drosophila, and INSR in human cells. This schematic summarizes the findings tein (which leads to enhanced during proteotoxic stress, in C. elegans, which are the most complete. Activation of DAF-2 activates a nuclear localization). CHN-1 is recruited toward misconserved signaling cascade that phosphorylates the FOXO transcription factor DAF-16, preventing its accumulation in the nucleus. Reducing DAF-2 The authors then go on folded proteins and away from signaling allows DAF-16 to accumulate in the nucleus and activate the tranto show biochemically how INSR/DAF-2, resulting in its scription of genes that promote longevity. DAF-2 protein turnover is regulated CHN-1 regulates IIS signaling stabilization. This effect of proby ubiquitylation by CHN-1. When CHN-1 is absent, the ubiquitylation sites of in C. elegans. By monitoring teotoxic stress on INSR also DAF-2 are mutated, or CHN-1 is redirected to misfolded proteins, the levels of the DAF-2 receptor are increased and lifespan is shortened. protein levels in vivo, they appears to be conserved. The find that the levels of DAF-2 authors show that inducing are elevated in chn-1 mutants, oxidative stress in Drosophila suggesting that loss of CHN-1 stabilizes Drosophila and human cells. Depletion of or introducing aggregation-prone polyglutthe protein. CHN-1 and DAF-2 interact both dCHIP and human CHIP increases amine proteins in human cells both result directly in immunoprecipitation assays, the phosphorylation of AKT, indicative of in INSR stabilization. This begs the quesand CHN-1 can efficiently ubiquitylate increased IIS signaling, and both dCHIP tion: if the proper levels of INSR/DAF-2 recombinant DAF-2 in vitro, suggesting and human CHIP can efficiently ubiquity- could be established by some other means, that CHN-1 controls DAF-2 levels by con- late INSRs. However, CHIP does not would proteotoxic stressors still limit trolling its turnover in vivo. The authors ubiquitylate a related receptor, the insu- lifespan? confirm this idea and demonstrate its lin-like growth factor receptor 1 (IGF1R), The capacity of the protein qualityimportance for lifespan, first by showing in vitro, and depletion of CHIP does not control network declines as the load of that a catalytically inactive form of CHN-1 stabilize IGFR1 in human cells. Similarly, misfolded proteins increases. Thus, the cannot rescue the shortened lifespan of in C. elegans, a related ubiquitin ligase, accumulation of damaged proteins with chn-1 and second by using mass spec- UFD-2, does not ubiquitylate DAF-2 age ends up overwhelming the proteostatrometry to identify the lysine residues of in vitro, and loss of ufd-2 does not stabi- sis machinery (David et al., 2010; Walther DAF-2 that are ubiquitylated in vitro. They lize DAF-2 in vivo. et al., 2015). Until now, the most straightgo on to identify a daf-2 allele that harbors The importance of this interaction for forward explanation was that a collapse a point mutation in one of these lysine lifespan may also be conserved. It has of proteostasis limits lifespan by the accuresidues and, remarkably, has a short previously been shown that mouse knock- mulation of toxic proteins and aggregates. lifespan, in contrast to daf-2 loss-of-func- outs of CHIP exhibit a shortened lifespan However, this study raises the intriguing tion mutants, which exhibit a dramatically (Min et al., 2008), and the study by Tawo possibility that a collapse of proteostasis increased lifespan. This point mutation, et al. (2017) now shows that RNAi- could limit lifespan simply by stabilizing which prevents CHN-1 ubiquitylation, mediated knockdown of Drosophila CHIP INSR/DAF-2 (Figure 1). Consistent with thus stabilizes the DAF-2 protein, similarly (dCHIP) also shortens lifespan. However, this interpretation, daf-2 loss-of-function to what is observed when chn-1 is ab- although it is tempting to speculate, it is mutants are very resistant to most, if not sent. Interestingly, this means that the dy- not yet known whether these lifespan ef- all, proteotoxic stresses (Honda and namics of DAF-2 receptor turnover alone fects are also due to INSR stabilization. Honda, 1999; Lithgow et al., 1995; Morley are sufficient to dictate the level of IIS As described above, the study by Tawo et al., 2002). It would be a true conceptual signaling and thereby regulate aging. et al. (2017) identifies a role for CHIP/ breakthrough if one could more rigorously The interaction between CHIP/CHN-1 CHN-1 in the direct ubiquitylation of the demonstrate that failure to maintain proand INSR/DAF-2 appears to be both spe- INSR/DAF-2. However, CHIP also has an teostasis does not itself reduce lifespan, cific and conserved. The authors show established role in general proteostasis by but instead acts via effects on the turnover that CHIP also regulates IIS signaling in interacting with the heat shock protein of INSR/DAF-2. Developmental Cell 41, April 24, 2017 127
Developmental Cell
Previews REFERENCES Connell, P., Ballinger, C.A., Jiang, J., Wu, Y., Thompson, L.J., Ho¨hfeld, J., and Patterson, C. (2001). Nat. Cell Biol. 3, 93–96. David, D.C., Ollikainen, N., Trinidad, J.C., Cary, M.P., Burlingame, A.L., and Kenyon, C. (2010). PLoS Biol. 8, e1000450. Honda, Y., and Honda, S. (1999). FASEB J. 13, 1385–1393.
128 Developmental Cell 41, April 24, 2017
Lithgow, G.J., White, T.M., Melov, S., and Johnson, T.E. (1995). Proc. Natl. Acad. Sci. USA 92, 7540–7544.
Tawo, R., Pokrzywa, W., Kevei, E., Akyuz, M.E., Balaji, V., Adrian, S., Hohfeld, J., and Hoppe, T. (2017). Cell 169, 470–482.
Min, J.N., Whaley, R.A., Sharpless, N.E., Lockyer, P., Portbury, A.L., and Patterson, C. (2008). Mol. Cell. Biol. 28, 4018–4025.
Vilchez, D., Saez, I., and Dillin, A. (2014). Nat. Commun. 5, 5659.
Morley, J.F., Brignull, H.R., Weyers, J.J., and Morimoto, R.I. (2002). Proc. Natl. Acad. Sci. USA 99, 10417–10422.
Walther, D.M., Kasturi, P., Zheng, M., Pinkert, S., Vecchi, G., Ciryam, P., Morimoto, R.I., Dobson, C.M., Vendruscolo, M., Mann, M., and Hartl, F.U. (2015). Cell 161, 919–932.
Previews more hypoxic (Jain, 2014). This highlights the need for appropriate and personalized dosing. The blood vessel normalization signature described by Tian and colleagues may help in identifying patients that will benefit from combination therapies. Finally, a major outstanding question relates to the molecular mechanism through which T lymphocytes promote blood vessel normalization. While the authors provide interesting clues relating to chemokine-induced attraction of pericytes that stabilize blood vessels, much of these findings remain correlative. Also, the differential effects that CD4+ and CD8+ T cells exert on the tumor vasculature and metastatic propensity are interesting topics for further analyses. This exciting and elegant study by Tian and colleagues
(2017) therefore opens the window to more detailed molecular and mechanistic studies of the signaling pathways that determine T lymphocyte-induced blood vessel normalization. Such complementary studies could reveal additional therapeutic targets that can be leveraged to achieve a better perfusion, as well as an enhanced immune response in tumors. REFERENCES
Huang, Y., Goel, S., Duda, D.G., Fukumura, D., and Jain, R.K. (2013). Cancer Res. 73, 2943–2948. Hugo, W., Zaretsky, J.M., Sun, L., Song, C., Moreno, B.H., Hu-Lieskovan, S., Berent-Maoz, B., Pang, J., Chmielowski, B., Cherry, G., et al. (2016). Cell 165, 35–44. Jain, R.K. (2014). Cancer Cell 26, 605–622. Keith, B., Johnson, R.S., and Simon, M.C. (2011). Nat. Rev. Cancer 12, 9–22. Thienpont, B., Steinbacher, J., Zhao, H., D’Anna, F., Kuchnio, A., Ploumakis, A., Ghesquie`re, B., Van Dyck, L., Boeckx, B., Schoonjans, L., et al. (2016). Nature 537, 63–68.
Carmeliet, P., and Jain, R.K. (2011). Nature 473, 298–307.
Tian, L., Goldstein, A., Wang, H., Lo, H.C., Kim, I.S., Welte, T., Sheng, K., Dobrolecki, L.E., Zhang, X., Putluri, N., et al. (2017). Nature. Published online April 3, 2017. http://dx.doi.org/10.1038/ nature21724.
Casazza, A., Di Conza, G., Wenes, M., Finisguerra, V., Deschoemaeker, S., and Mazzone, M. (2014). Oncogene 33, 1743–1754.
Wallin, J.J., Bendell, J.C., Funke, R., Sznol, M., Korski, K., Jones, S., Hernandez, G., Mier, J., He, X., Hodi, F.S., et al. (2016). Nat. Commun. 7, 12624.
Blank, C.U., Haanen, J.B., Ribas, A., and Schumacher, T.N. (2016). Science 352, 658–660.
Proteostasis or Aging: Let the CHIPs Fall Where They May Robyn Branicky1 and Siegfried Hekimi1,* 1Department of Biology, McGill University, Montreal H3A 1B1, Canada *Correspondence: [email protected] http://dx.doi.org/10.1016/j.devcel.2017.04.006
The conserved E3 ubiquitin ligase CHIP/CHN-1 contributes to proteostasis by ubiquitylating HSP70 and HSP90-interacting proteins. In a recent issue of Cell, Tawo et al. (2017) show that CHIP/CHN-1 also directly ubiquitylates the insulin receptor INSR/DAF-2 to regulate its turnover. These findings suggest an unexpected interpretation of the effects of altered proteostasis on survival. Proteostasis is maintained by an extensive quality-control network that promotes correct protein folding and degrades misfolded and aggregated proteins. It has long been observed that aging is associated with a decline in proteostasis, whereas enhanced proteostasis might be capable of increasing survival (Vilchez et al., 2014). However, it is not clear whether protein misfolding is causal to aging and, if so, whether the effect is due to the toxicity of the aberrant proteins or aggregates. A recent paper in Cell from Tawo et al. (2017) sheds light on this question. Changes in the activity of the conserved insulin/IGF-1 signaling pathway (IIS) are well known to affect the aging pro-
cess in a variety of organisms. Tawo et al. (2017) show that CHN-1, a conserved E3 ubiquitin ligase, directly ubiquitylates the insulin receptor DAF-2 in C. elegans. They also find that upon proteotoxic stress, the levels of DAF-2 are increased. This results in an upregulation of IIS signaling, which shortens lifespan. They suggest that under proteotoxic stress CHN-1 is redirected from DAF-2 to misfolded proteins, thus preventing ubiquitylation of DAF-2 and limiting lifespan. Importantly, this phenomenon appears to be conserved. Indeed, both the Drosophila (dCHIP) and human (CHIP) ligases ubiquitylate the insulin receptors (dINSR and INSR, respectively), and in both systems, proteotoxic stress
126 Developmental Cell 41, April 24, 2017 ª 2017 Elsevier Inc.
leads to increased levels of receptor protein. These findings suggest a mechanism for how protein aggregation might limit lifespan, one not based principally on the toxicity of misfolded proteins or protein aggregates. Initial observations by Tawo et al. (2017) suggested that chn-1, which encodes the C. elegans ortholog of CHIP, interacts genetically with the IIS signaling pathway. Activation of the IGF-1/INSR receptor (DAF-2 in C. elegans) activates a conserved PI3-kinase/AKT signaling cascade that phosphorylates FOXO transcription factors, preventing their accumulation in the nucleus. Reducing IIS signaling allows FOXO to accumulate in the nucleus and
Developmental Cell
Previews activate the transcription of chaperones HSP70 and No CHN-1 genes that promote longevity. HSP90 and promoting the or Low DAF-2 loss of DAF-2 Ub site Wild type Tawo et al. (2017) find that ubiquitylation and proteasomal or levels loss of C. elegans chn-1 indegradation of the proteins to proteotoxic stress creases IIS signaling: in chn-1 which they bind (Connell mutants, nuclear localization et al., 2001). Consistent with Ub Ub Ub DAF-2/INSR DAF-2/INSR DAF-2/INSR of the FOXO transcription CHN-1 also having this funcfactor DAF-16 is reduced, as tion, Tawo et al. (2017) find is transcription of its target that C. elegans chn-1 mutants genes. Accordingly, chn-1 are sensitive to heat stress, DAF-16/FOXO DAF-16/FOXO DAF-16/FOXO mutants have a reduced lifeoxidative stress, and the presspan. Indeed, further genetic ence of aggregation-prone analysis confirms the idea proteins, all of which are known Normal Increased Decreased that chn-1 acts via daf-16: the to be proteotoxic. A key finding Lifespan Lifespan Lifespan authors found that the reduced of the paper, which links these lifespan in chn-1 mutants is not functions, is that in the presFigure 1. Regulation of Lifespan via Ubiquitylaton of the Insulin enhanced by loss of daf-16 ence of CHN-1 all these Receptor and can be overcome by overstressors result in elevated The authors identify a conserved role for the E3 ubiquitin ligase CHIP/dCHIP/ CHN-1 in ubiquitylating the insulin receptor: DAF-2 in C. elegans, dINSR in expression of the DAF-16 proDAF-2 levels, suggesting that Drosophila, and INSR in human cells. This schematic summarizes the findings tein (which leads to enhanced during proteotoxic stress, in C. elegans, which are the most complete. Activation of DAF-2 activates a nuclear localization). CHN-1 is recruited toward misconserved signaling cascade that phosphorylates the FOXO transcription factor DAF-16, preventing its accumulation in the nucleus. Reducing DAF-2 The authors then go on folded proteins and away from signaling allows DAF-16 to accumulate in the nucleus and activate the tranto show biochemically how INSR/DAF-2, resulting in its scription of genes that promote longevity. DAF-2 protein turnover is regulated CHN-1 regulates IIS signaling stabilization. This effect of proby ubiquitylation by CHN-1. When CHN-1 is absent, the ubiquitylation sites of in C. elegans. By monitoring teotoxic stress on INSR also DAF-2 are mutated, or CHN-1 is redirected to misfolded proteins, the levels of the DAF-2 receptor are increased and lifespan is shortened. protein levels in vivo, they appears to be conserved. The find that the levels of DAF-2 authors show that inducing are elevated in chn-1 mutants, oxidative stress in Drosophila suggesting that loss of CHN-1 stabilizes Drosophila and human cells. Depletion of or introducing aggregation-prone polyglutthe protein. CHN-1 and DAF-2 interact both dCHIP and human CHIP increases amine proteins in human cells both result directly in immunoprecipitation assays, the phosphorylation of AKT, indicative of in INSR stabilization. This begs the quesand CHN-1 can efficiently ubiquitylate increased IIS signaling, and both dCHIP tion: if the proper levels of INSR/DAF-2 recombinant DAF-2 in vitro, suggesting and human CHIP can efficiently ubiquity- could be established by some other means, that CHN-1 controls DAF-2 levels by con- late INSRs. However, CHIP does not would proteotoxic stressors still limit trolling its turnover in vivo. The authors ubiquitylate a related receptor, the insu- lifespan? confirm this idea and demonstrate its lin-like growth factor receptor 1 (IGF1R), The capacity of the protein qualityimportance for lifespan, first by showing in vitro, and depletion of CHIP does not control network declines as the load of that a catalytically inactive form of CHN-1 stabilize IGFR1 in human cells. Similarly, misfolded proteins increases. Thus, the cannot rescue the shortened lifespan of in C. elegans, a related ubiquitin ligase, accumulation of damaged proteins with chn-1 and second by using mass spec- UFD-2, does not ubiquitylate DAF-2 age ends up overwhelming the proteostatrometry to identify the lysine residues of in vitro, and loss of ufd-2 does not stabi- sis machinery (David et al., 2010; Walther DAF-2 that are ubiquitylated in vitro. They lize DAF-2 in vivo. et al., 2015). Until now, the most straightgo on to identify a daf-2 allele that harbors The importance of this interaction for forward explanation was that a collapse a point mutation in one of these lysine lifespan may also be conserved. It has of proteostasis limits lifespan by the accuresidues and, remarkably, has a short previously been shown that mouse knock- mulation of toxic proteins and aggregates. lifespan, in contrast to daf-2 loss-of-func- outs of CHIP exhibit a shortened lifespan However, this study raises the intriguing tion mutants, which exhibit a dramatically (Min et al., 2008), and the study by Tawo possibility that a collapse of proteostasis increased lifespan. This point mutation, et al. (2017) now shows that RNAi- could limit lifespan simply by stabilizing which prevents CHN-1 ubiquitylation, mediated knockdown of Drosophila CHIP INSR/DAF-2 (Figure 1). Consistent with thus stabilizes the DAF-2 protein, similarly (dCHIP) also shortens lifespan. However, this interpretation, daf-2 loss-of-function to what is observed when chn-1 is ab- although it is tempting to speculate, it is mutants are very resistant to most, if not sent. Interestingly, this means that the dy- not yet known whether these lifespan ef- all, proteotoxic stresses (Honda and namics of DAF-2 receptor turnover alone fects are also due to INSR stabilization. Honda, 1999; Lithgow et al., 1995; Morley are sufficient to dictate the level of IIS As described above, the study by Tawo et al., 2002). It would be a true conceptual signaling and thereby regulate aging. et al. (2017) identifies a role for CHIP/ breakthrough if one could more rigorously The interaction between CHIP/CHN-1 CHN-1 in the direct ubiquitylation of the demonstrate that failure to maintain proand INSR/DAF-2 appears to be both spe- INSR/DAF-2. However, CHIP also has an teostasis does not itself reduce lifespan, cific and conserved. The authors show established role in general proteostasis by but instead acts via effects on the turnover that CHIP also regulates IIS signaling in interacting with the heat shock protein of INSR/DAF-2. Developmental Cell 41, April 24, 2017 127
Developmental Cell
Previews REFERENCES Connell, P., Ballinger, C.A., Jiang, J., Wu, Y., Thompson, L.J., Ho¨hfeld, J., and Patterson, C. (2001). Nat. Cell Biol. 3, 93–96. David, D.C., Ollikainen, N., Trinidad, J.C., Cary, M.P., Burlingame, A.L., and Kenyon, C. (2010). PLoS Biol. 8, e1000450. Honda, Y., and Honda, S. (1999). FASEB J. 13, 1385–1393.
128 Developmental Cell 41, April 24, 2017
Lithgow, G.J., White, T.M., Melov, S., and Johnson, T.E. (1995). Proc. Natl. Acad. Sci. USA 92, 7540–7544.
Tawo, R., Pokrzywa, W., Kevei, E., Akyuz, M.E., Balaji, V., Adrian, S., Hohfeld, J., and Hoppe, T. (2017). Cell 169, 470–482.
Min, J.N., Whaley, R.A., Sharpless, N.E., Lockyer, P., Portbury, A.L., and Patterson, C. (2008). Mol. Cell. Biol. 28, 4018–4025.
Vilchez, D., Saez, I., and Dillin, A. (2014). Nat. Commun. 5, 5659.
Morley, J.F., Brignull, H.R., Weyers, J.J., and Morimoto, R.I. (2002). Proc. Natl. Acad. Sci. USA 99, 10417–10422.
Walther, D.M., Kasturi, P., Zheng, M., Pinkert, S., Vecchi, G., Ciryam, P., Morimoto, R.I., Dobson, C.M., Vendruscolo, M., Mann, M., and Hartl, F.U. (2015). Cell 161, 919–932.