Crosstalk Between Biomolecular Condensates and Proteostasis

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2022 Aug 12

PMID 35954258

Authors

Emmanuel Amzallag

Eran Hornstein

Affiliations

Soon will be listed here.

Abstract

Proper homeostasis of the proteome, referred to as proteostasis, is maintained by chaperone-dependent refolding of misfolded proteins and by protein degradation via the ubiquitin-proteasome system and the autophagic machinery. This review will discuss a crosstalk between biomolecular condensates and proteostasis, whereby the crowding of proteostasis factors into macromolecular assemblies is often established by phase separation of membraneless biomolecular condensates. Specifically, ubiquitin and other posttranslational modifications come into play as agents of phase separation, essential for the formation of condensates and for ubiquitin-proteasome system activity. Furthermore, an intriguing connection associates malfunction of the same pathways to the accumulation of misfolded and ubiquitinated proteins in aberrant condensates, the formation of protein aggregates, and finally, to the pathogenesis of neurodegenerative diseases. The crosstalk between biomolecular condensates and proteostasis is an emerging theme in cellular and disease biology and further studies will focus on delineating specific molecular pathways involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases.

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References

Maxwell B, Gwon Y, Mishra A, Peng J, Nakamura H, Zhang K . Ubiquitination is essential for recovery of cellular activities after heat shock. Science. 2021; 372(6549):eabc3593. PMC: 8574219. DOI: 10.1126/science.abc3593. View

Marmor-Kollet H, Siany A, Kedersha N, Knafo N, Rivkin N, Danino Y . Spatiotemporal Proteomic Analysis of Stress Granule Disassembly Using APEX Reveals Regulation by SUMOylation and Links to ALS Pathogenesis. Mol Cell. 2020; 80(5):876-891.e6. PMC: 7816607. DOI: 10.1016/j.molcel.2020.10.032. View

Kwon Y, Ciechanover A . The Ubiquitin Code in the Ubiquitin-Proteasome System and Autophagy. Trends Biochem Sci. 2017; 42(11):873-886. DOI: 10.1016/j.tibs.2017.09.002. View

Deng H, Zhai H, Bigio E, Yan J, Fecto F, Ajroud K . FUS-immunoreactive inclusions are a common feature in sporadic and non-SOD1 familial amyotrophic lateral sclerosis. Ann Neurol. 2010; 67(6):739-48. PMC: 4376270. DOI: 10.1002/ana.22051. View

Deng H, Chen W, Hong S, Boycott K, Gorrie G, Siddique N . Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature. 2011; 477(7363):211-5. PMC: 3169705. DOI: 10.1038/nature10353. View

Sun D, Wu R, Zheng J, Li P, Yu L . Polyubiquitin chain-induced p62 phase separation drives autophagic cargo segregation. Cell Res. 2018; 28(4):405-415. PMC: 5939046. DOI: 10.1038/s41422-018-0017-7. View

Zhang Y, Gendron T, Ebbert M, ORaw A, Yue M, Jansen-West K . Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. Nat Med. 2018; 24(8):1136-1142. PMC: 6520050. DOI: 10.1038/s41591-018-0071-1. View

Walters R, Muhlrad D, Garcia J, Parker R . Differential effects of Ydj1 and Sis1 on Hsp70-mediated clearance of stress granules in Saccharomyces cerevisiae. RNA. 2015; 21(9):1660-71. PMC: 4536325. DOI: 10.1261/rna.053116.115. View

Hartl F, Bracher A, Hayer-Hartl M . Molecular chaperones in protein folding and proteostasis. Nature. 2011; 475(7356):324-32. DOI: 10.1038/nature10317. View

10.

Kedersha N, Anderson P . Regulation of translation by stress granules and processing bodies. Prog Mol Biol Transl Sci. 2010; 90:155-85. PMC: 7102815. DOI: 10.1016/S1877-1173(09)90004-7. View

11.

Ciryam P, Tartaglia G, Morimoto R, Dobson C, Vendruscolo M . Widespread aggregation and neurodegenerative diseases are associated with supersaturated proteins. Cell Rep. 2013; 5(3):781-90. PMC: 3883113. DOI: 10.1016/j.celrep.2013.09.043. View

12.

Keiten-Schmitz J, Roder L, Hornstein E, Muller-McNicoll M, Muller S . SUMO: Glue or Solvent for Phase-Separated Ribonucleoprotein Complexes and Molecular Condensates?. Front Mol Biosci. 2021; 8:673038. PMC: 8138125. DOI: 10.3389/fmolb.2021.673038. View

13.

Li Y, King O, Shorter J, Gitler A . Stress granules as crucibles of ALS pathogenesis. J Cell Biol. 2013; 201(3):361-72. PMC: 3639398. DOI: 10.1083/jcb.201302044. View

14.

Hayes E, Sirvio L, Ye Y . A Potential Mechanism for Targeting Aggregates With Proteasomes and Disaggregases in Liquid Droplets. Front Aging Neurosci. 2022; 14:854380. PMC: 9062979. DOI: 10.3389/fnagi.2022.854380. View

15.

Gwon Y, Maxwell B, Kolaitis R, Zhang P, Kim H, Taylor J . Ubiquitination of G3BP1 mediates stress granule disassembly in a context-specific manner. Science. 2021; 372(6549):eabf6548. PMC: 8574224. DOI: 10.1126/science.abf6548. View

16.

Basso M, Samengo G, Nardo G, Massignan T, DAlessandro G, Tartari S . Characterization of detergent-insoluble proteins in ALS indicates a causal link between nitrative stress and aggregation in pathogenesis. PLoS One. 2009; 4(12):e8130. PMC: 2780298. DOI: 10.1371/journal.pone.0008130. View

17.

Xie X, Matsumoto S, Endo A, Fukushima T, Kawahara H, Saeki Y . Deubiquitylases USP5 and USP13 are recruited to and regulate heat-induced stress granules through their deubiquitylating activities. J Cell Sci. 2018; 131(8). DOI: 10.1242/jcs.210856. View

18.

Samanta N, Ribeiro S, Becker M, Laborie E, Pollak R, Timr S . Sequestration of Proteins in Stress Granules Relies on the In-Cell but Not the Folding Stability. J Am Chem Soc. 2021; 143(47):19909-19918. DOI: 10.1021/jacs.1c09589. View

19.

Dao T, Kolaitis R, Kim H, ODonovan K, Martyniak B, Colicino E . Ubiquitin Modulates Liquid-Liquid Phase Separation of UBQLN2 via Disruption of Multivalent Interactions. Mol Cell. 2018; 69(6):965-978.e6. PMC: 6181577. DOI: 10.1016/j.molcel.2018.02.004. View

20.

VanPelt J, Page R . Unraveling the CHIP:Hsp70 complex as an information processor for protein quality control. Biochim Biophys Acta Proteins Proteom. 2016; 1865(2):133-141. DOI: 10.1016/j.bbapap.2016.11.005. View