Abstract
The discovery of ubiquitin conjugation to lysines and the role of K48-linked polyubiquitin in targeting substrates for proteasomal degradation was followed by revelation of non-degradative roles of ubiquitination and, more recently, of non-canonical covalent ubiquitin linkages. Here we summarize findings of the ever-expanding array of ubiquitin signals and their biological roles.
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References
Goldstein, G. et al. Isolation of a polypeptide that has lymphocyte-differentiating properties and is probably represented universally in living cells. Proc. Natl Acad. Sci. USA 72, 11 (1975).
Goldknopf, I. L. & Busch, H. Isopeptide linkage between nonhistone and histone 2A polypeptides of chromosomal conjugate-protein A24. Proc. Natl Acad. Sci. USA 74, 864–868 (1977).
Levinger, L. & Varshavsky, A. Selective arrangement of ubiquitinated and D1 protein-containing nucleosomes within the drosophila genome. Cell 28, 375–385 (1982).
Ciechanover, A., Heller, H., Elias, S., Haas, A. L. & Hershko, A. ATP-dependent conjugation of reticulocyte proteins with the polypeptide required for protein degradation. Proc. Natl Acad. Sci. USA 77, 1365–1368 (1980).
Hershko, A., Ciechanover, A., Heller, H., Haas, A. L. & Rose, I. A. Proposed role of ATP in protein breakdown: conjugation of protein with multiple chains of the polypeptide of ATP-dependent proteolysis. Proc. Natl Acad. Sci. USA 77, 1783–1786 (1980).
Wilkinson, K. D., Urban, M. K. & Haas, A. L. Ubiquitin is the ATP-dependent proteolysis factor I of rabbit reticulocytes. J. Biol. Chem. 255, 7529–7532 (1980).
Hershko, A., Heller, H., Elias, S. & Ciechanover, A. Components of ubiquitin-protein ligase system. Resolution, affinity purification, and role in protein breakdown. J. Biol. Chem. 258, 8206–8214 (1983).
Chau, V. et al. A multiubiquitin chain is confined to specific lysine in a targeted short-lived protein. Science 243, 1576–1583 (1989).
Hofmann, R. M. & Pickart, C. M. Noncanonical MMS2-encoded ubiquitin-conjugating enzyme functions in assembly of novel polyubiquitin chains for DNA repair. Cell 96, 645–653 (1999).
Spence, J., Sadis, S., Haas, A. L. & Finley, D. A ubiquitin mutant with specific defects in DNA repair and multiubiquitination. Mol. Cell. Biol. 15, 1265–1273 (1995).
VanDemark, A. P., Hofmann, R. M., Tsui, C., Pickart, C. M. & Wolberger, C. Molecular insights into polyubiquitin chain assembly: crystal structure of the Mms2/Ubc13 heterodimer. Cell 105, 711–720 (2001).
Eddins, M. J., Carlile, C. M., Gomez, K. M., Pickart, C. M. & Wolberger, C. Mms2–Ubc13 covalently bound to ubiquitin reveals the structural basis of linkage-specific polyubiquitin chain formation. Nat. Struct. Mol. Biol. 13, 915–920 (2006).
de Napoles, M. et al. Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation. Dev. Cell 7, 663–676 (2004).
Wang, H. et al. Role of histone H2A ubiquitination in Polycomb silencing. Nature 431, 873–878 (2004).
Cooper, S. et al. Jarid2 binds mono-ubiquitylated H2A lysine 119 to mediate crosstalk between Polycomb complexes PRC1 and PRC2. Nat. Commun. 7, 13661 (2016).
Sun, Z.-W. & Allis, C. D. Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast. Nature 418, 104–108 (2002).
Briggs, S. D. et al. Trans-histone regulatory pathway in chromatin. Nature 418, 498 (2002).
Fradet-Turcotte, A. et al. 53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark. Nature 499, 50–54 (2013).
Worden, E. J., Hoffmann, N. A., Hicks, C. W. & Wolberger, C. Mechanism of cross-talk between H2B ubiquitination and H3 methylation by Dot1L. Cell 176, 1490–1501 (2019).
Kasinath, V. et al. JARID2 and AEBP2 regulate PRC2 in the presence of H2AK119ub1 and other histone modifications. Science 371, eabc3393 (2021).
Rahman, S. et al. Multistate structures of the MLL1-WRAD complex bound to H2B-ubiquitinated nucleosome. Proc. Natl Acad. Sci. USA 119, e2205691119 (2022).
Kirisako, T. et al. A ubiquitin ligase complex assembles linear polyubiquitin chains. EMBO J. 25, 4877–4887 (2006).
Fiil, B. K. & Gyrd-Hansen, M. The Met1-linked ubiquitin machinery in inflammation and infection. Cell Death Differ. 28, 557–569 (2021).
Pao, K.-C. et al. Activity-based E3 ligase profiling uncovers an E3 ligase with esterification activity. Nature 556, 381–385 (2018).
Kelsall, I. R., Zhang, J., Knebel, A., Arthur, J. S. C. & Cohen, P. The E3 ligase HOIL-1 catalyses ester bond formation between ubiquitin and components of the Myddosome in mammalian cells. Proc. Natl Acad. Sci. USA 116, 13293–13298 (2019).
Qiu, J. et al. Ubiquitination independent of E1 and E2 enzymes by bacterial effectors. Nature 533, 120–124 (2016).
Otten, E. G. et al. Ubiquitylation of lipopolysaccharide by RNF213 during bacterial infection. Nature 594, 111–116 (2021).
Acknowledgements
This work was supported by a NIH grant GM130393 (C.W.) and fellowship CA271743 (S.R.).
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Rahman, S., Wolberger, C. Breaking the K48-chain: linking ubiquitin beyond protein degradation. Nat Struct Mol Biol 31, 216–218 (2024). https://doi.org/10.1038/s41594-024-01221-w
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DOI: https://doi.org/10.1038/s41594-024-01221-w