Emerging Roles of Ubiquitination in Biomolecular Condensates
<p>Stress-granule dynamics are tightly regulated by ubiquitination. Cells under stress inhibit the translation initiation of mRNAs, leading to stress granules’ formation that involves the phase separation of RBPs (such as G3BP1, T-cell intracellular antigen 1 (TIA-1), ELAV-like protein 1 (HuR), TIA1-related protein (TIAR) etc.) and mRNAs. Both the assembly and disassembly of stress granules are regulated by PTMs, including ubiquitination. The disassembly of stress granules is enhanced through the K63-linked ubiquitination of G3BP1, subsequently fostering the interaction between ubiquitin chains and VCP. Mutations in RBPs or prolonged stress cause the transition of stress granules into pathological aggregates. Ubiquitination governs the clearance of these aggregates, with K48-linked ubiquitin chains directing degradation through the ubiquitin-proteasome system (UPS), whereas K63-linked ubiquitination is associated with the autophagic degradation pathways. Created with BioRender.com.</p> "> Figure 2
<p>The process of autophagic cargo segregation is driven by poly-ubiquitin chain-induced p62 phase separation. p62 protein forms oligomers via the PB1 domain and also binds to ubiquitin through the UBA domain. Upon reaching the threshold concentration required for LLPS, the formation of p62 condensates occurs. Subsequently, other client proteins are recruited to these p62 condensates that further mature and ultimately are broken down through autophagy. Created with BioRender.com.</p> ">
Abstract
:1. Introduction
2. Ubiquitin in Stress Granule Dynamics
3. Ubiquitin in Autophagy
4. Ubiquitin in Other Biomolecular Condensates
5. Summary and Future Perspectives
Biomolecular Condensates | Ubiquitin | Effect on Phase Separation | Reference |
---|---|---|---|
Arsenite, or heat-induced stress granules | Poly-ubiquitin | Promotes LLPS | [30] |
Heat-induced stress granules | Mono-ubiquitin | Causes disassembly | [28] |
Arsenite, or heat-induced stress granules | K63 poly-ubiquitin | Causes disassembly | [34,43] |
p62 condensates | Poly-ubiquitin | Promotes LLPS | [70] |
p62 condensates | Mono-ubiquitin | Causes disassembly | [69] |
Proteasome condensate | Mono-ubiquitin | Causes disassembly | [116] |
UBQLN2 phase separation | Poly-ubiquitin | Causes disassembly | [31] |
Dvl2 phase separation | Poly-ubiquitin | Promotes LLPS | [104] |
NEMO phase separation | Poly-ubiquitin | Promotes LLPS | [100] |
Author Contributions
Funding
Conflicts of Interest
References
- Banani, S.F.; Lee, H.O.; Hyman, A.A.; Rosen, M.K. Biomolecular condensates: Organizers of cellular biochemistry. Nat. Rev. Mol. Cell Biol. 2017, 18, 285–298. [Google Scholar] [CrossRef] [PubMed]
- Boeynaems, S.; Alberti, S.; Fawzi, N.L.; Mittag, T.; Polymenidou, M.; Rousseau, F.; Schymkowitz, J.; Shorter, J.; Wolozin, B.; Van Den Bosch, L.; et al. Protein Phase Separation: A New Phase in Cell Biology. Trends Cell Biol. 2018, 28, 420–435. [Google Scholar] [CrossRef] [PubMed]
- Alberti, S.; Dormann, D. Liquid-Liquid Phase Separation in Disease. Annu. Rev. Genet. 2019, 53, 171–194. [Google Scholar] [CrossRef]
- Shin, Y.; Brangwynne, C.P. Liquid phase condensation in cell physiology and disease. Science 2017, 357, eaaf4382. [Google Scholar] [CrossRef] [PubMed]
- Zhang, H.; Ji, X.; Li, P.; Liu, C.; Lou, J.; Wang, Z.; Wen, W.; Xiao, Y.; Zhang, M.; Zhu, X. Liquid-liquid phase separation in biology: Mechanisms, physiological functions and human diseases. Sci. China Life Sci. 2020, 63, 953–985. [Google Scholar] [CrossRef]
- Li, J.; Zhang, M.; Ma, W.; Yang, B.; Lu, H.; Zhou, F.; Zhang, L. Post-translational modifications in liquid-liquid phase separation: A comprehensive review. Mol. Biomed. 2022, 3, 13. [Google Scholar] [CrossRef]
- Swatek, K.N.; Komander, D. Ubiquitin modifications. Cell Res. 2016, 26, 399–422. [Google Scholar] [CrossRef]
- Husnjak, K.; Dikic, I. Ubiquitin-binding proteins: Decoders of ubiquitin-mediated cellular functions. Annu. Rev. Biochem. 2012, 81, 291–322. [Google Scholar] [CrossRef]
- Yau, R.; Rape, M. The increasing complexity of the ubiquitin code. Nat. Cell Biol. 2016, 18, 579–586. [Google Scholar] [CrossRef]
- Manohar, S.; Jacob, S.; Wang, J.; Wiechecki, K.A.; Koh, H.W.L.; Simoes, V.; Choi, H.; Vogel, C.; Silva, G.M. Polyubiquitin Chains Linked by Lysine Residue 48 (K48) Selectively Target Oxidized Proteins In Vivo. Antioxid. Redox Signal 2019, 31, 1133–1149. [Google Scholar] [CrossRef]
- Meerang, M.; Ritz, D.; Paliwal, S.; Garajova, Z.; Bosshard, M.; Mailand, N.; Janscak, P.; Hubscher, U.; Meyer, H.; Ramadan, K. The ubiquitin-selective segregase VCP/p97 orchestrates the response to DNA double-strand breaks. Nat. Cell Biol. 2011, 13, 1376–1382. [Google Scholar] [CrossRef]
- Madiraju, C.; Novack, J.P.; Reed, J.C.; Matsuzawa, S.I. K63 ubiquitination in immune signaling. Trends Immunol. 2022, 43, 148–162. [Google Scholar] [CrossRef]
- Chen, J.; Chen, Z.J. Regulation of NF-kappaB by ubiquitination. Curr. Opin. Immunol. 2013, 25, 4–12. [Google Scholar] [CrossRef] [PubMed]
- Dosa, A.; Csizmadia, T. The role of K63-linked polyubiquitin in several types of autophagy. Biol. Futur. 2022, 73, 137–148. [Google Scholar] [CrossRef] [PubMed]
- Tracz, M.; Bialek, W. Beyond K48 and K63: Non-canonical protein ubiquitination. Cell Mol. Biol. Lett. 2021, 26, 1. [Google Scholar] [CrossRef]
- Pickrell, A.M.; Youle, R.J. The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson’s disease. Neuron 2015, 85, 257–273. [Google Scholar] [CrossRef]
- Ordureau, A.; Heo, J.M.; Duda, D.M.; Paulo, J.A.; Olszewski, J.L.; Yanishevski, D.; Rinehart, J.; Schulman, B.A.; Harper, J.W. Defining roles of PARKIN and ubiquitin phosphorylation by PINK1 in mitochondrial quality control using a ubiquitin replacement strategy. Proc. Natl. Acad. Sci. USA 2015, 112, 6637–6642. [Google Scholar] [CrossRef] [PubMed]
- Castaneda, C.A.; Kashyap, T.R.; Nakasone, M.A.; Krueger, S.; Fushman, D. Unique structural, dynamical, and functional properties of k11-linked polyubiquitin chains. Structure 2013, 21, 1168–1181. [Google Scholar] [CrossRef]
- Wu-Baer, F.; Lagrazon, K.; Yuan, W.; Baer, R. The BRCA1/BARD1 heterodimer assembles polyubiquitin chains through an unconventional linkage involving lysine residue K6 of ubiquitin. J. Biol. Chem. 2003, 278, 34743–34746. [Google Scholar] [CrossRef] [PubMed]
- Wickliffe, K.E.; Williamson, A.; Meyer, H.J.; Kelly, A.; Rape, M. K11-linked ubiquitin chains as novel regulators of cell division. Trends Cell Biol. 2011, 21, 656–663. [Google Scholar] [CrossRef]
- Wu, X.; Lei, C.; Xia, T.; Zhong, X.; Yang, Q.; Shu, H.B. Regulation of TRIF-mediated innate immune response by K27-linked polyubiquitination and deubiquitination. Nat. Commun. 2019, 10, 4115. [Google Scholar] [CrossRef] [PubMed]
- Buchan, J.R.; Parker, R. Eukaryotic stress granules: The ins and outs of translation. Mol. Cell 2009, 36, 932–941. [Google Scholar] [CrossRef] [PubMed]
- Kedersha, N.; Stoecklin, G.; Ayodele, M.; Yacono, P.; Lykke-Andersen, J.; Fritzler, M.J.; Scheuner, D.; Kaufman, R.J.; Golan, D.E.; Anderson, P. Stress granules and processing bodies are dynamically linked sites of mRNP remodeling. J. Cell Biol. 2005, 169, 871–884. [Google Scholar] [CrossRef] [PubMed]
- Jain, S.; Wheeler, J.R.; Walters, R.W.; Agrawal, A.; Barsic, A.; Parker, R. ATPase-Modulated Stress Granules Contain a Diverse Proteome and Substructure. Cell 2016, 164, 487–498. [Google Scholar] [CrossRef]
- Kedersha, N.L.; Gupta, M.; Li, W.; Miller, I.; Anderson, P. RNA-binding proteins TIA-1 and TIAR link the phosphorylation of eIF-2 alpha to the assembly of mammalian stress granules. J. Cell Biol. 1999, 147, 1431–1442. [Google Scholar] [CrossRef]
- Ohn, T.; Anderson, P. The role of posttranslational modifications in the assembly of stress granules. Wiley Interdiscip. Rev. RNA 2010, 1, 486–493. [Google Scholar] [CrossRef]
- Turakhiya, A.; Meyer, S.R.; Marincola, G.; Bohm, S.; Vanselow, J.T.; Schlosser, A.; Hofmann, K.; Buchberger, A. ZFAND1 Recruits p97 and the 26S Proteasome to Promote the Clearance of Arsenite-Induced Stress Granules. Mol. Cell 2018, 70, 906–919.e7. [Google Scholar] [CrossRef]
- Xie, X.; Matsumoto, S.; Endo, A.; Fukushima, T.; Kawahara, H.; Saeki, Y.; Komada, M. Deubiquitylases USP5 and USP13 are recruited to and regulate heat-induced stress granules through their deubiquitylating activities. J. Cell Sci. 2018, 131, jcs210856. [Google Scholar] [CrossRef]
- Takahashi, M.; Kitaura, H.; Kakita, A.; Kakihana, T.; Katsuragi, Y.; Onodera, O.; Iwakura, Y.; Nawa, H.; Komatsu, M.; Fujii, M. USP10 Inhibits Aberrant Cytoplasmic Aggregation of TDP-43 by Promoting Stress Granule Clearance. Mol. Cell Biol. 2022, 42, e0039321. [Google Scholar] [CrossRef]
- Kwon, S.; Zhang, Y.; Matthias, P. The deacetylase HDAC6 is a novel critical component of stress granules involved in the stress response. Genes. Dev. 2007, 21, 3381–3394. [Google Scholar] [CrossRef]
- Dao, T.P.; Kolaitis, R.M.; Kim, H.J.; O’Donovan, K.; Martyniak, B.; Colicino, E.; Hehnly, H.; Taylor, J.P.; Castaneda, C.A. Ubiquitin Modulates Liquid-Liquid Phase Separation of UBQLN2 via Disruption of Multivalent Interactions. Mol. Cell 2018, 69, 965–978.e6. [Google Scholar] [CrossRef] [PubMed]
- Wang, B.; Maxwell, B.A.; Joo, J.H.; Gwon, Y.; Messing, J.; Mishra, A.; Shaw, T.I.; Ward, A.L.; Quan, H.; Sakurada, S.M.; et al. ULK1 and ULK2 Regulate Stress Granule Disassembly Through Phosphorylation and Activation of VCP/p97. Mol. Cell 2019, 74, 742–757.e8. [Google Scholar] [CrossRef] [PubMed]
- Valdez-Sinon, A.N.; Lai, A.; Shi, L.; Lancaster, C.L.; Gokhale, A.; Faundez, V.; Bassell, G.J. Cdh1-APC Regulates Protein Synthesis and Stress Granules in Neurons through an FMRP-Dependent Mechanism. iScience 2020, 23, 101132. [Google Scholar] [CrossRef]
- Yang, C.; Wang, Z.; Kang, Y.; Yi, Q.; Wang, T.; Bai, Y.; Liu, Y. Stress granule homeostasis is modulated by TRIM21-mediated ubiquitination of G3BP1 and autophagy-dependent elimination of stress granules. Autophagy 2023, 19, 1934–1951. [Google Scholar] [CrossRef]
- Buchan, J.R.; Kolaitis, R.M.; Taylor, J.P.; Parker, R. Eukaryotic stress granules are cleared by autophagy and Cdc48/VCP function. Cell 2013, 153, 1461–1474. [Google Scholar] [CrossRef] [PubMed]
- Markmiller, S.; Fulzele, A.; Higgins, R.; Leonard, M.; Yeo, G.W.; Bennett, E.J. Active Protein Neddylation or Ubiquitylation Is Dispensable for Stress Granule Dynamics. Cell Rep. 2019, 27, 1356–1363.e3. [Google Scholar] [CrossRef]
- Maxwell, B.A.; Gwon, Y.; Mishra, A.; Peng, J.; Nakamura, H.; Zhang, K.; Kim, H.J.; Taylor, J.P. Ubiquitination is essential for recovery of cellular activities after heat shock. Science 2021, 372, eabc3593. [Google Scholar] [CrossRef]
- Tolay, N.; Buchberger, A. Comparative profiling of stress granule clearance reveals differential contributions of the ubiquitin system. Life Sci. Alliance 2021, 4, e202000927. [Google Scholar] [CrossRef]
- Itakura, E.; Zavodszky, E.; Shao, S.; Wohlever, M.L.; Keenan, R.J.; Hegde, R.S. Ubiquilins Chaperone and Triage Mitochondrial Membrane Proteins for Degradation. Mol. Cell 2016, 63, 21–33. [Google Scholar] [CrossRef]
- Alexander, E.J.; Ghanbari Niaki, A.; Zhang, T.; Sarkar, J.; Liu, Y.; Nirujogi, R.S.; Pandey, A.; Myong, S.; Wang, J. Ubiquilin 2 modulates ALS/FTD-linked FUS-RNA complex dynamics and stress granule formation. Proc. Natl. Acad. Sci. USA 2018, 115, E11485–E11494. [Google Scholar] [CrossRef]
- Peng, G.; Gu, A.; Niu, H.; Chen, L.; Chen, Y.; Zhou, M.; Zhang, Y.; Liu, J.; Cai, L.; Liang, D.; et al. Amyotrophic lateral sclerosis (ALS) linked mutation in Ubiquilin 2 affects stress granule assembly via TIA-1. CNS Neurosci. Ther. 2022, 28, 105–115. [Google Scholar] [CrossRef] [PubMed]
- Hook, S.S.; Orian, A.; Cowley, S.M.; Eisenman, R.N. Histone deacetylase 6 binds polyubiquitin through its zinc finger (PAZ domain) and copurifies with deubiquitinating enzymes. Proc. Natl. Acad. Sci. USA 2002, 99, 13425–13430. [Google Scholar] [CrossRef] [PubMed]
- Gwon, Y.; Maxwell, B.A.; Kolaitis, R.M.; Zhang, P.; Kim, H.J.; Taylor, J.P. Ubiquitination of G3BP1 mediates stress granule disassembly in a context-specific manner. Science 2021, 372, eabf6548. [Google Scholar] [CrossRef] [PubMed]
- Keiten-Schmitz, J.; Wagner, K.; Piller, T.; Kaulich, M.; Alberti, S.; Muller, S. The Nuclear SUMO-Targeted Ubiquitin Quality Control Network Regulates the Dynamics of Cytoplasmic Stress Granules. Mol. Cell 2020, 79, 54–67.e7. [Google Scholar] [CrossRef]
- Baradaran-Heravi, Y.; Van Broeckhoven, C.; van der Zee, J. Stress granule mediated protein aggregation and underlying gene defects in the FTD-ALS spectrum. Neurobiol. Dis. 2020, 134, 104639. [Google Scholar] [CrossRef] [PubMed]
- Ripin, N.; Parker, R. Are stress granules the RNA analogs of misfolded protein aggregates? RNA 2022, 28, 67–75. [Google Scholar] [CrossRef] [PubMed]
- Taylor, J.P.; Brown, R.H., Jr.; Cleveland, D.W. Decoding ALS: From genes to mechanism. Nature 2016, 539, 197–206. [Google Scholar] [CrossRef]
- Neumann, M.; Sampathu, D.M.; Kwong, L.K.; Truax, A.C.; Micsenyi, M.C.; Chou, T.T.; Bruce, J.; Schuck, T.; Grossman, M.; Clark, C.M.; et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006, 314, 130–133. [Google Scholar] [CrossRef] [PubMed]
- Bruijn, L.I.; Becher, M.W.; Lee, M.K.; Anderson, K.L.; Jenkins, N.A.; Copeland, N.G.; Sisodia, S.S.; Rothstein, J.D.; Borchelt, D.R.; Price, D.L.; et al. ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 1997, 18, 327–338. [Google Scholar] [CrossRef]
- Boyko, S.; Surewicz, W.K. Tau liquid-liquid phase separation in neurodegenerative diseases. Trends Cell Biol. 2022, 32, 611–623. [Google Scholar] [CrossRef]
- Parolini, F.; Tira, R.; Barracchia, C.G.; Munari, F.; Capaldi, S.; D’Onofrio, M.; Assfalg, M. Ubiquitination of Alzheimer’s-related tau protein affects liquid-liquid phase separation in a site- and cofactor-dependent manner. Int. J. Biol. Macromol. 2022, 201, 173–181. [Google Scholar] [CrossRef] [PubMed]
- Dikic, I.; Elazar, Z. Mechanism and medical implications of mammalian autophagy. Nat. Rev. Mol. Cell Biol. 2018, 19, 349–364. [Google Scholar] [CrossRef] [PubMed]
- Mizushima, N.; Komatsu, M. Autophagy: Renovation of cells and tissues. Cell 2011, 147, 728–741. [Google Scholar] [CrossRef]
- Levine, B.; Kroemer, G. Autophagy in the pathogenesis of disease. Cell 2008, 132, 27–42. [Google Scholar] [CrossRef] [PubMed]
- Goodall, E.A.; Kraus, F.; Harper, J.W. Mechanisms underlying ubiquitin-driven selective mitochondrial and bacterial autophagy. Mol. Cell 2022, 82, 1501–1513. [Google Scholar] [CrossRef]
- Chu, Y.; Kang, Y.; Yan, C.; Yang, C.; Zhang, T.; Huo, H.; Liu, Y. LUBAC and OTULIN regulate autophagy initiation and maturation by mediating the linear ubiquitination and the stabilization of ATG13. Autophagy 2021, 17, 1684–1699. [Google Scholar] [CrossRef]
- Varshavsky, A. The Ubiquitin System, Autophagy, and Regulated Protein Degradation. Annu. Rev. Biochem. 2017, 86, 123–128. [Google Scholar] [CrossRef]
- Liu, C.C.; Lin, Y.C.; Chen, Y.H.; Chen, C.M.; Pang, L.Y.; Chen, H.A.; Wu, P.R.; Lin, M.Y.; Jiang, S.T.; Tsai, T.F.; et al. Cul3-KLHL20 Ubiquitin Ligase Governs the Turnover of ULK1 and VPS34 Complexes to Control Autophagy Termination. Mol. Cell 2016, 61, 84–97. [Google Scholar] [CrossRef]
- Fujioka, Y.; Noda, N.N. Biomolecular condensates in autophagy regulation. Curr. Opin. Cell Biol. 2021, 69, 23–29. [Google Scholar] [CrossRef]
- Noda, N.N.; Wang, Z.; Zhang, H. Liquid-liquid phase separation in autophagy. J. Cell Biol. 2020, 219, e202004062. [Google Scholar] [CrossRef]
- Lu, Y.; Chang, C. Phase Separation in Regulation of Autophagy. Front. Cell Dev. Biol. 2022, 10, 910640. [Google Scholar] [CrossRef] [PubMed]
- Yamasaki, A.; Alam, J.M.; Noshiro, D.; Hirata, E.; Fujioka, Y.; Suzuki, K.; Ohsumi, Y.; Noda, N.N. Liquidity Is a Critical Determinant for Selective Autophagy of Protein Condensates. Mol. Cell 2020, 77, 1163–1175.e9. [Google Scholar] [CrossRef] [PubMed]
- Feng, Y.; He, D.; Yao, Z.; Klionsky, D.J. The machinery of macroautophagy. Cell Res. 2014, 24, 24–41. [Google Scholar] [CrossRef] [PubMed]
- Fujioka, Y.; Alam, J.M.; Noshiro, D.; Mouri, K.; Ando, T.; Okada, Y.; May, A.I.; Knorr, R.L.; Suzuki, K.; Ohsumi, Y.; et al. Phase separation organizes the site of autophagosome formation. Nature 2020, 578, 301–305. [Google Scholar] [CrossRef]
- Shi, X.; Chang, C.; Yokom, A.L.; Jensen, L.E.; Hurley, J.H. The autophagy adaptor NDP52 and the FIP200 coiled-coil allosterically activate ULK1 complex membrane recruitment. Elife 2020, 9, e59099. [Google Scholar] [CrossRef]
- Pankiv, S.; Clausen, T.H.; Lamark, T.; Brech, A.; Bruun, J.A.; Outzen, H.; Overvatn, A.; Bjorkoy, G.; Johansen, T. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J. Biol. Chem. 2007, 282, 24131–24145. [Google Scholar] [CrossRef]
- Danieli, A.; Martens, S. p62-mediated phase separation at the intersection of the ubiquitin-proteasome system and autophagy. J. Cell Sci. 2018, 131, jcs214304. [Google Scholar] [CrossRef]
- Kumar, A.V.; Mills, J.; Lapierre, L.R. Selective Autophagy Receptor p62/SQSTM1, a Pivotal Player in Stress and Aging. Front. Cell Dev. Biol. 2022, 10, 793328. [Google Scholar] [CrossRef]
- Zaffagnini, G.; Savova, A.; Danieli, A.; Romanov, J.; Tremel, S.; Ebner, M.; Peterbauer, T.; Sztacho, M.; Trapannone, R.; Tarafder, A.K.; et al. p62 filaments capture and present ubiquitinated cargos for autophagy. EMBO J. 2018, 37, e98308. [Google Scholar] [CrossRef]
- Sun, D.; Wu, R.; Zheng, J.; Li, P.; Yu, L. Polyubiquitin chain-induced p62 phase separation drives autophagic cargo segregation. Cell Res. 2018, 28, 405–415. [Google Scholar] [CrossRef]
- Ciuffa, R.; Lamark, T.; Tarafder, A.K.; Guesdon, A.; Rybina, S.; Hagen, W.J.; Johansen, T.; Sachse, C. The selective autophagy receptor p62 forms a flexible filamentous helical scaffold. Cell Rep. 2015, 11, 748–758. [Google Scholar] [CrossRef] [PubMed]
- Herhaus, L.; Dikic, I. Ubiquitin-induced phase separation of p62/SQSTM1. Cell Res. 2018, 28, 389–390. [Google Scholar] [CrossRef]
- Peng, H.; Yang, J.; Li, G.; You, Q.; Han, W.; Li, T.; Gao, D.; Xie, X.; Lee, B.H.; Du, J.; et al. Ubiquitylation of p62/sequestosome1 activates its autophagy receptor function and controls selective autophagy upon ubiquitin stress. Cell Res. 2017, 27, 657–674. [Google Scholar] [CrossRef] [PubMed]
- Rasmussen, N.L.; Kournoutis, A.; Lamark, T.; Johansen, T. NBR1: The archetypal selective autophagy receptor. J. Cell Biol. 2022, 221, e202208092. [Google Scholar] [CrossRef] [PubMed]
- Adriaenssens, E.; Ferrari, L.; Martens, S. Orchestration of selective autophagy by cargo receptors. Curr. Biol. 2022, 32, R1357–R1371. [Google Scholar] [CrossRef]
- Turco, E.; Savova, A.; Gere, F.; Ferrari, L.; Romanov, J.; Schuschnig, M.; Martens, S. Reconstitution defines the roles of p62, NBR1 and TAX1BP1 in ubiquitin condensate formation and autophagy initiation. Nat. Commun. 2021, 12, 5212. [Google Scholar] [CrossRef]
- Vargas, J.N.S.; Hamasaki, M.; Kawabata, T.; Youle, R.J.; Yoshimori, T. The mechanisms and roles of selective autophagy in mammals. Nat. Rev. Mol. Cell Biol. 2023, 24, 167–185. [Google Scholar] [CrossRef]
- Peng, S.Z.; Chen, X.H.; Chen, S.J.; Zhang, J.; Wang, C.Y.; Liu, W.R.; Zhang, D.; Su, Y.; Zhang, X.K. Phase separation of Nur77 mediates celastrol-induced mitophagy by promoting the liquidity of p62/SQSTM1 condensates. Nat. Commun. 2021, 12, 5989. [Google Scholar] [CrossRef]
- Odeh, H.M.; Shorter, J. Aggregates of TDP-43 protein spiral into view. Nature 2022, 601, 29–30. [Google Scholar] [CrossRef]
- Wegmann, S.; Eftekharzadeh, B.; Tepper, K.; Zoltowska, K.M.; Bennett, R.E.; Dujardin, S.; Laskowski, P.R.; MacKenzie, D.; Kamath, T.; Commins, C.; et al. Tau protein liquid-liquid phase separation can initiate tau aggregation. EMBO J. 2018, 37, e98049. [Google Scholar] [CrossRef]
- Jo, M.; Lee, S.; Jeon, Y.M.; Kim, S.; Kwon, Y.; Kim, H.J. The role of TDP-43 propagation in neurodegenerative diseases: Integrating insights from clinical and experimental studies. Exp. Mol. Med. 2020, 52, 1652–1662. [Google Scholar] [CrossRef] [PubMed]
- Teyssou, E.; Takeda, T.; Lebon, V.; Boillee, S.; Doukoure, B.; Bataillon, G.; Sazdovitch, V.; Cazeneuve, C.; Meininger, V.; LeGuern, E.; et al. Mutations in SQSTM1 encoding p62 in amyotrophic lateral sclerosis: Genetics and neuropathology. Acta Neuropathol. 2013, 125, 511–522. [Google Scholar] [CrossRef] [PubMed]
- Kwok, C.T.; Morris, A.; de Belleroche, J.S. Sequestosome-1 (SQSTM1) sequence variants in ALS cases in the UK: Prevalence and coexistence of SQSTM1 mutations in ALS kindred with PDB. Eur. J. Hum. Genet. 2014, 22, 492–496. [Google Scholar] [CrossRef]
- Dessay, M.; Jobin Gervais, F.; Simonyan, D.; Samson, A.; Gleeton, G.; Gagnon, E.; Albert, C.; Brown, J.P.; Michou, L. Clinical phenotype of adult offspring carriers of the p.Pro392Leu mutation within the SQSTM1 gene in Paget’s disease of bone. Bone Rep. 2020, 13, 100717. [Google Scholar] [CrossRef] [PubMed]
- Rea, S.L.; Walsh, J.P.; Layfield, R.; Ratajczak, T.; Xu, J. New insights into the role of sequestosome 1/p62 mutant proteins in the pathogenesis of Paget’s disease of bone. Endocr. Rev. 2013, 34, 501–524. [Google Scholar] [CrossRef]
- Deng, Z.; Lim, J.; Wang, Q.; Purtell, K.; Wu, S.; Palomo, G.M.; Tan, H.; Manfredi, G.; Zhao, Y.; Peng, J.; et al. ALS-FTLD-linked mutations of SQSTM1/p62 disrupt selective autophagy and NFE2L2/NRF2 anti-oxidative stress pathway. Autophagy 2020, 16, 917–931. [Google Scholar] [CrossRef]
- Spector, D.L.; Lamond, A.I. Nuclear speckles. Cold Spring Harb. Perspect. Biol. 2011, 3, a000646. [Google Scholar] [CrossRef]
- Ilik, I.A.; Malszycki, M.; Lubke, A.K.; Schade, C.; Meierhofer, D.; Aktas, T. SON and SRRM2 are essential for nuclear speckle formation. Elife 2020, 9, e60579. [Google Scholar] [CrossRef]
- Xu, S.; Lai, S.K.; Sim, D.Y.; Ang, W.S.L.; Li, H.Y.; Roca, X. SRRM2 organizes splicing condensates to regulate alternative splicing. Nucleic Acids Res. 2022, 50, 8599–8614. [Google Scholar] [CrossRef]
- Cuneo, M.J.; Mittag, T. The ubiquitin ligase adaptor SPOP in cancer. FEBS J. 2019, 286, 3946–3958. [Google Scholar] [CrossRef]
- Bouchard, J.J.; Otero, J.H.; Scott, D.C.; Szulc, E.; Martin, E.W.; Sabri, N.; Granata, D.; Marzahn, M.R.; Lindorff-Larsen, K.; Salvatella, X.; et al. Cancer Mutations of the Tumor Suppressor SPOP Disrupt the Formation of Active, Phase-Separated Compartments. Mol. Cell 2018, 72, 19–36.e8. [Google Scholar] [CrossRef] [PubMed]
- Marzahn, M.R.; Marada, S.; Lee, J.; Nourse, A.; Kenrick, S.; Zhao, H.; Ben-Nissan, G.; Kolaitis, R.M.; Peters, J.L.; Pounds, S.; et al. Higher-order oligomerization promotes localization of SPOP to liquid nuclear speckles. EMBO J. 2016, 35, 1254–1275. [Google Scholar] [CrossRef]
- Liu, S.; Wang, T.; Shi, Y.; Bai, L.; Wang, S.; Guo, D.; Zhang, Y.; Qi, Y.; Chen, C.; Zhang, J.; et al. USP42 drives nuclear speckle mRNA splicing via directing dynamic phase separation to promote tumorigenesis. Cell Death Differ. 2021, 28, 2482–2498. [Google Scholar] [CrossRef] [PubMed]
- Yasuda, S.; Tsuchiya, H.; Kaiho, A.; Guo, Q.; Ikeuchi, K.; Endo, A.; Arai, N.; Ohtake, F.; Murata, S.; Inada, T.; et al. Stress- and ubiquitylation-dependent phase separation of the proteasome. Nature 2020, 578, 296–300. [Google Scholar] [CrossRef] [PubMed]
- Laporte, D.; Salin, B.; Daignan-Fornier, B.; Sagot, I. Reversible cytoplasmic localization of the proteasome in quiescent yeast cells. J. Cell Biol. 2008, 181, 737–745. [Google Scholar] [CrossRef] [PubMed]
- Gu, Z.C.; Wu, E.; Sailer, C.; Jando, J.; Styles, E.; Eisenkolb, I.; Kuschel, M.; Bitschar, K.; Wang, X.; Huang, L.; et al. Ubiquitin orchestrates proteasome dynamics between proliferation and quiescence in yeast. Mol. Biol. Cell 2017, 28, 2479–2491. [Google Scholar] [CrossRef]
- Laporte, D.; Lebaudy, A.; Sahin, A.; Pinson, B.; Ceschin, J.; Daignan-Fornier, B.; Sagot, I. Metabolic status rather than cell cycle signals control quiescence entry and exit. J. Cell Biol. 2011, 192, 949–957. [Google Scholar] [CrossRef]
- Enenkel, C.; Kang, R.W.; Wilfling, F.; Ernst, O.P. Intracellular localization of the proteasome in response to stress conditions. J. Biol. Chem. 2022, 298, 102083. [Google Scholar] [CrossRef]
- Liu, T.; Zhang, L.; Joo, D.; Sun, S.C. NF-kappaB signaling in inflammation. Signal Transduct. Target. Ther. 2017, 2, 17023. [Google Scholar] [CrossRef]
- Du, M.; Ea, C.K.; Fang, Y.; Chen, Z.J. Liquid phase separation of NEMO induced by polyubiquitin chains activates NF-kappaB. Mol. Cell 2022, 82, 2415–2426.e5. [Google Scholar] [CrossRef]
- Goel, S.; Oliva, R.; Jeganathan, S.; Bader, V.; Krause, L.J.; Kriegler, S.; Stender, I.D.; Christine, C.W.; Nakamura, K.; Hoffmann, J.E.; et al. Linear ubiquitination induces NEMO phase separation to activate NF-kappaB signaling. Life Sci. Alliance 2023, 6, e202201607. [Google Scholar] [CrossRef] [PubMed]
- Hua, F.; Hao, W.; Wang, L.; Li, S. Linear Ubiquitination Mediates EGFR-Induced NF-kappaB Pathway and Tumor Development. Int. J. Mol. Sci. 2021, 22, 11875. [Google Scholar] [CrossRef] [PubMed]
- Lee, Y.N.; Gao, Y.; Wang, H.Y. Differential mediation of the Wnt canonical pathway by mammalian Dishevelleds-1, -2, and -3. Cell Signal 2008, 20, 443–452. [Google Scholar] [CrossRef] [PubMed]
- Vamadevan, V.; Chaudhary, N.; Maddika, S. Ubiquitin-assisted phase separation of dishevelled-2 promotes Wnt signalling. J. Cell Sci. 2022, 135, jcs260284. [Google Scholar] [CrossRef]
- LoPresti, P. HDAC6 in Diseases of Cognition and of Neurons. Cells 2020, 10, 12. [Google Scholar] [CrossRef]
- Simoes-Pires, C.; Zwick, V.; Nurisso, A.; Schenker, E.; Carrupt, P.A.; Cuendet, M. HDAC6 as a target for neurodegenerative diseases: What makes it different from the other HDACs? Mol. Neurodegener. 2013, 8, 7. [Google Scholar] [CrossRef]
- Trzeciakiewicz, H.; Ajit, D.; Tseng, J.H.; Chen, Y.; Ajit, A.; Tabassum, Z.; Lobrovich, R.; Peterson, C.; Riddick, N.V.; Itano, M.S.; et al. An HDAC6-dependent surveillance mechanism suppresses tau-mediated neurodegeneration and cognitive decline. Nat. Commun. 2020, 11, 5522. [Google Scholar] [CrossRef]
- Pandey, U.B.; Nie, Z.; Batlevi, Y.; McCray, B.A.; Ritson, G.P.; Nedelsky, N.B.; Schwartz, S.L.; DiProspero, N.A.; Knight, M.A.; Schuldiner, O.; et al. HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 2007, 447, 859–863. [Google Scholar] [CrossRef]
- Govindarajan, N.; Rao, P.; Burkhardt, S.; Sananbenesi, F.; Schluter, O.M.; Bradke, F.; Lu, J.; Fischer, A. Reducing HDAC6 ameliorates cognitive deficits in a mouse model for Alzheimer’s disease. EMBO Mol. Med. 2013, 5, 52–63. [Google Scholar] [CrossRef]
- Yoo, Y.E.; Ko, C.P. Treatment with trichostatin A initiated after disease onset delays disease progression and increases survival in a mouse model of amyotrophic lateral sclerosis. Exp. Neurol. 2011, 231, 147–159. [Google Scholar] [CrossRef]
- Ma, S.; Attarwala, I.Y.; Xie, X.Q. SQSTM1/p62: A Potential Target for Neurodegenerative Disease. ACS Chem. Neurosci. 2019, 10, 2094–2114. [Google Scholar] [CrossRef] [PubMed]
- Bjorkoy, G.; Lamark, T.; Brech, A.; Outzen, H.; Perander, M.; Overvatn, A.; Stenmark, H.; Johansen, T. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J. Cell Biol. 2005, 171, 603–614. [Google Scholar] [CrossRef] [PubMed]
- Davidson, J.M.; Chung, R.S.; Lee, A. The converging roles of sequestosome-1/p62 in the molecular pathways of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neurobiol. Dis. 2022, 166, 105653. [Google Scholar] [CrossRef] [PubMed]
- Kedersha, N.; Panas, M.D.; Achorn, C.A.; Lyons, S.; Tisdale, S.; Hickman, T.; Thomas, M.; Lieberman, J.; McInerney, G.M.; Ivanov, P.; et al. G3BP-Caprin1-USP10 complexes mediate stress granule condensation and associate with 40S subunits. J. Cell Biol. 2016, 212, 845–860. [Google Scholar] [CrossRef]
- Bello, A.I.; Goswami, R.; Brown, S.L.; Costanzo, K.; Shores, T.; Allan, S.; Odah, R.; Mohan, R.D. Deubiquitinases in Neurodegeneration. Cells 2022, 11, 556. [Google Scholar] [CrossRef]
- Song, A.; Hazlett, Z.; Abeykoon, D.; Dortch, J.; Dillon, A.; Curtiss, J.; Martinez, S.B.; Hill, C.P.; Yu, C.; Huang, L.; et al. Branched ubiquitin chain binding and deubiquitination by UCH37 facilitate proteasome clearance of stress-induced inclusions. eLife 2021, 10, e72798. [Google Scholar] [CrossRef] [PubMed]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Liang, P.; Zhang, J.; Wang, B. Emerging Roles of Ubiquitination in Biomolecular Condensates. Cells 2023, 12, 2329. https://doi.org/10.3390/cells12182329
Liang P, Zhang J, Wang B. Emerging Roles of Ubiquitination in Biomolecular Condensates. Cells. 2023; 12(18):2329. https://doi.org/10.3390/cells12182329
Chicago/Turabian StyleLiang, Peigang, Jiaqi Zhang, and Bo Wang. 2023. "Emerging Roles of Ubiquitination in Biomolecular Condensates" Cells 12, no. 18: 2329. https://doi.org/10.3390/cells12182329