Multi-Step Ubiquitin Decoding Mechanism for Proteasomal Degradation

Overview

Journal Pharmaceuticals (Basel)

Publisher MDPI

Specialty Chemistry

Date 2020 Jun 27

PMID 32585960

Citations 4

Authors

Hikaru Tsuchiya

Akinori Endo

Yasushi Saeki

Affiliations

Soon will be listed here.

Abstract

The 26S proteasome is a 2.5-MDa protease complex responsible for the selective and ATP-dependent degradation of ubiquitylated proteins in eukaryotic cells. Proteasome-mediated protein degradation accounts for ~70% of all cellular proteolysis under basal conditions, and thereby any dysfunction can lead to drastic changes in cell homeostasis. A major function of ubiquitylation is to target proteins for proteasomal degradation. Accompanied by deciphering the structural diversity of ubiquitin chains with eight linkages and chain lengths, the ubiquitin code for proteasomal degradation has been expanding beyond the best-characterized Lys48-linked ubiquitin chains. Whereas polyubiquitylated proteins can be directly recognized by the proteasome, in several cases, these proteins need to be extracted or segregated by the conserved ATPases associated with diverse cellular activities (AAA)-family ATPase p97/valosin-containing protein (VCP) complex and escorted to the proteasome by ubiquitin-like (UBL)-ubiquitin associated (UBA) proteins; these are called substrate-shuttling factors. Furthermore, proteasomes are highly mobile and are appropriately spatiotemporally regulated in response to different cellular environments and stresses. In this review, we highlight an emerging key link between p97, shuttling factors, and proteasome for efficient proteasomal degradation. We also present evidence that proteasome-containing nuclear foci form by liquid-liquid phase separation under acute hyperosmotic stress.

Citing Articles

Occupancy of the HbYX hydrophobic pocket is sufficient to induce gate opening in the archaeal 20S proteasomes.

Chuah J, Daugherty M, Smith D bioRxiv. 2024; .

PMID: 38826226 PMC: 11142061. DOI: 10.1101/2024.05.21.595185.

New Scaffolds of Proteasome Inhibitors: Boosting Anticancer Potential by Exploiting the Synergy of In Silico and In Vitro Methodologies.

Guedes R, Grilo J, Carvalho A, Fernandes P, Ressurreicao A, Brito V Pharmaceuticals (Basel). 2023; 16(8).

PMID: 37631011 PMC: 10458307. DOI: 10.3390/ph16081096.

Current methodologies in protein ubiquitination characterization: from ubiquitinated protein to ubiquitin chain architecture.

Sun M, Zhang X Cell Biosci. 2022; 12(1):126.

PMID: 35962460 PMC: 9373315. DOI: 10.1186/s13578-022-00870-y.

Placental gene networks at the interface between maternal PM exposure early in gestation and reduced infant birthweight.

Deyssenroth M, Rosa M, Eliot M, Kelsey K, Kloog I, Schwartz J Environ Res. 2021; 199:111342.

PMID: 34015297 PMC: 8195860. DOI: 10.1016/j.envres.2021.111342.

References

Verma R, Oania R, Graumann J, Deshaies R . Multiubiquitin chain receptors define a layer of substrate selectivity in the ubiquitin-proteasome system. Cell. 2004; 118(1):99-110. DOI: 10.1016/j.cell.2004.06.014. View

Prakash S, Tian L, Ratliff K, Lehotzky R, Matouschek A . An unstructured initiation site is required for efficient proteasome-mediated degradation. Nat Struct Mol Biol. 2004; 11(9):830-7. DOI: 10.1038/nsmb814. View

Raasi S, Varadan R, Fushman D, Pickart C . Diverse polyubiquitin interaction properties of ubiquitin-associated domains. Nat Struct Mol Biol. 2005; 12(8):708-14. DOI: 10.1038/nsmb962. View

Yasuda S, Tsuchiya H, Kaiho A, Guo Q, Ikeuchi K, Endo A . Stress- and ubiquitylation-dependent phase separation of the proteasome. Nature. 2020; 578(7794):296-300. DOI: 10.1038/s41586-020-1982-9. View

Ng J, Vrieling H, Sugasawa K, Ooms M, Grootegoed J, Vreeburg J . Developmental defects and male sterility in mice lacking the ubiquitin-like DNA repair gene mHR23B. Mol Cell Biol. 2002; 22(4):1233-45. PMC: 134644. DOI: 10.1128/MCB.22.4.1233-1245.2002. View

Samant R, Livingston C, Sontag E, Frydman J . Distinct proteostasis circuits cooperate in nuclear and cytoplasmic protein quality control. Nature. 2018; 563(7731):407-411. PMC: 6707801. DOI: 10.1038/s41586-018-0678-x. View

Li P, Banjade S, Cheng H, Kim S, Chen B, Guo L . Phase transitions in the assembly of multivalent signalling proteins. Nature. 2012; 483(7389):336-40. PMC: 3343696. DOI: 10.1038/nature10879. 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

Raasi S, Orlov I, Fleming K, Pickart C . Binding of polyubiquitin chains to ubiquitin-associated (UBA) domains of HHR23A. J Mol Biol. 2004; 341(5):1367-79. DOI: 10.1016/j.jmb.2004.06.057. View

10.

Perozzi G, Prakash S . RAD7 gene of Saccharomyces cerevisiae: transcripts, nucleotide sequence analysis, and functional relationship between the RAD7 and RAD23 gene products. Mol Cell Biol. 1986; 6(5):1497-507. PMC: 367675. DOI: 10.1128/mcb.6.5.1497-1507.1986. View

11.

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

12.

Yip M, Bodnar N, Rapoport T . Ddi1 is a ubiquitin-dependent protease. Proc Natl Acad Sci U S A. 2020; 117(14):7776-7781. PMC: 7149228. DOI: 10.1073/pnas.1902298117. View

13.

Ohtake F, Tsuchiya H, Tanaka K, Saeki Y . Methods to measure ubiquitin chain length and linkage. Methods Enzymol. 2019; 618:105-133. DOI: 10.1016/bs.mie.2018.12.019. View

14.

Shabek N, Herman-Bachinsky Y, Buchsbaum S, Lewinson O, Haj-Yahya M, Hejjaoui M . The size of the proteasomal substrate determines whether its degradation will be mediated by mono- or polyubiquitylation. Mol Cell. 2012; 48(1):87-97. DOI: 10.1016/j.molcel.2012.07.011. View

15.

Koizumi S, Irie T, Hirayama S, Sakurai Y, Yashiroda H, Naguro I . The aspartyl protease DDI2 activates Nrf1 to compensate for proteasome dysfunction. Elife. 2016; 5. PMC: 5001836. DOI: 10.7554/eLife.18357. View

16.

Sung M, Porras-Yakushi T, Reitsma J, Huber F, Sweredoski M, Hoelz A . A conserved quality-control pathway that mediates degradation of unassembled ribosomal proteins. Elife. 2016; 5. PMC: 5026473. DOI: 10.7554/eLife.19105. View

17.

Sato Y, Yoshikawa A, Yamashita M, Yamagata A, Fukai S . Structural basis for specific recognition of Lys 63-linked polyubiquitin chains by NZF domains of TAB2 and TAB3. EMBO J. 2009; 28(24):3903-9. PMC: 2797061. DOI: 10.1038/emboj.2009.345. View

18.

Sakata E, Bohn S, Mihalache O, Kiss P, Beck F, Nagy I . Localization of the proteasomal ubiquitin receptors Rpn10 and Rpn13 by electron cryomicroscopy. Proc Natl Acad Sci U S A. 2012; 109(5):1479-84. PMC: 3277190. DOI: 10.1073/pnas.1119394109. View

19.

Kajava A . What curves alpha-solenoids? Evidence for an alpha-helical toroid structure of Rpn1 and Rpn2 proteins of the 26 S proteasome. J Biol Chem. 2002; 277(51):49791-8. DOI: 10.1074/jbc.M204982200. View

20.

Wilkinson C, Seeger M, Hartmann-Petersen R, Stone M, Wallace M, Semple C . Proteins containing the UBA domain are able to bind to multi-ubiquitin chains. Nat Cell Biol. 2001; 3(10):939-43. DOI: 10.1038/ncb1001-939. View