The Predator Becomes the Prey: Regulating the Ubiquitin System by Ubiquitylation and Degradation

Overview

Journal Nat Rev Mol Cell Biol

Specialties Cell Biology
Molecular Biology

Date 2011 Aug 24

PMID 21860393

Citations 140

Authors

Allan M Weissman

Nitzan Shabek

Aaron Ciechanover

Affiliations

Soon will be listed here.

Abstract

Ubiquitylation (also known as ubiquitination) regulates essentially all of the intracellular processes in eukaryotes through highly specific modification of numerous cellular proteins, which is often tightly regulated in a spatial and temporal manner. Although most often associated with proteasomal degradation, ubiquitylation frequently serves non-proteolytic functions. In light of its central roles in cellular regulation, it has not been surprising to find that many of the components of the ubiquitin system itself are regulated by ubiquitylation. This observation has broad implications for pathophysiology.

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References

Linares L, Hengstermann A, Ciechanover A, Muller S, Scheffner M . HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53. Proc Natl Acad Sci U S A. 2003; 100(21):12009-14. PMC: 218704. DOI: 10.1073/pnas.2030930100. View

Boutell C, Canning M, Orr A, Everett R . Reciprocal activities between herpes simplex virus type 1 regulatory protein ICP0, a ubiquitin E3 ligase, and ubiquitin-specific protease USP7. J Virol. 2005; 79(19):12342-54. PMC: 1211536. DOI: 10.1128/JVI.79.19.12342-12354.2005. View

Bajorek M, Finley D, Glickman M . Proteasome disassembly and downregulation is correlated with viability during stationary phase. Curr Biol. 2003; 13(13):1140-4. DOI: 10.1016/s0960-9822(03)00417-2. View

Leggett D, Hanna J, Borodovsky A, Crosas B, Schmidt M, Baker R . Multiple associated proteins regulate proteasome structure and function. Mol Cell. 2002; 10(3):495-507. DOI: 10.1016/s1097-2765(02)00638-x. View

Fu J, Jin Y, Arend L . Smac3, a novel Smac/DIABLO splicing variant, attenuates the stability and apoptosis-inhibiting activity of X-linked inhibitor of apoptosis protein. J Biol Chem. 2003; 278(52):52660-72. DOI: 10.1074/jbc.M308036200. View

Mouchantaf R, Azakir B, McPherson P, Millard S, Wood S, Angers A . The ubiquitin ligase itch is auto-ubiquitylated in vivo and in vitro but is protected from degradation by interacting with the deubiquitylating enzyme FAM/USP9X. J Biol Chem. 2006; 281(50):38738-47. DOI: 10.1074/jbc.M605959200. View

Wilkinson K . The discovery of ubiquitin-dependent proteolysis. Proc Natl Acad Sci U S A. 2005; 102(43):15280-2. PMC: 1266097. DOI: 10.1073/pnas.0504842102. View

Kimura Y, Yashiroda H, Kudo T, Koitabashi S, Murata S, Kakizuka A . An inhibitor of a deubiquitinating enzyme regulates ubiquitin homeostasis. Cell. 2009; 137(3):549-59. DOI: 10.1016/j.cell.2009.02.028. View

Di Fiore B, Pines J . Defining the role of Emi1 in the DNA replication-segregation cycle. Chromosoma. 2008; 117(4):333-8. DOI: 10.1007/s00412-008-0152-x. View

10.

Patel M, Majetschak M . Distribution and interrelationship of ubiquitin proteasome pathway component activities and ubiquitin pools in various porcine tissues. Physiol Res. 2006; 56(3):341-350. DOI: 10.33549/physiolres.931005. View

11.

Carroll S, Hampton R . Usa1p is required for optimal function and regulation of the Hrd1p endoplasmic reticulum-associated degradation ubiquitin ligase. J Biol Chem. 2009; 285(8):5146-56. PMC: 2820741. DOI: 10.1074/jbc.M109.067876. View

12.

Kreft S, Hochstrasser M . An unusual transmembrane helix in the endoplasmic reticulum ubiquitin ligase Doa10 modulates degradation of its cognate E2 enzyme. J Biol Chem. 2011; 286(23):20163-74. PMC: 3121455. DOI: 10.1074/jbc.M110.196360. View

13.

Shabek N, Herman-Bachinsky Y, Ciechanover A . Ubiquitin degradation with its substrate, or as a monomer in a ubiquitination-independent mode, provides clues to proteasome regulation. Proc Natl Acad Sci U S A. 2009; 106(29):11907-12. PMC: 2715473. DOI: 10.1073/pnas.0905746106. View

14.

Verhoef L, Heinen C, Selivanova A, Halff E, Salomons F, Dantuma N . Minimal length requirement for proteasomal degradation of ubiquitin-dependent substrates. FASEB J. 2008; 23(1):123-33. DOI: 10.1096/fj.08-115055. View

15.

Hanna J, Leggett D, Finley D . Ubiquitin depletion as a key mediator of toxicity by translational inhibitors. Mol Cell Biol. 2003; 23(24):9251-61. PMC: 309641. DOI: 10.1128/MCB.23.24.9251-9261.2003. View

16.

Linke K, Mace P, Smith C, Vaux D, Silke J, Day C . Structure of the MDM2/MDMX RING domain heterodimer reveals dimerization is required for their ubiquitylation in trans. Cell Death Differ. 2008; 15(5):841-8. DOI: 10.1038/sj.cdd.4402309. View

17.

Ying Z, Wang H, Fan H, Zhu X, Zhou J, Fei E . Gp78, an ER associated E3, promotes SOD1 and ataxin-3 degradation. Hum Mol Genet. 2009; 18(22):4268-81. DOI: 10.1093/hmg/ddp380. View

18.

Scheffner M, Huibregtse J, Vierstra R, Howley P . The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell. 1993; 75(3):495-505. DOI: 10.1016/0092-8674(93)90384-3. View

19.

Lee J, Song B, DeBose-Boyd R, Ye J . Sterol-regulated degradation of Insig-1 mediated by the membrane-bound ubiquitin ligase gp78. J Biol Chem. 2006; 281(51):39308-15. DOI: 10.1074/jbc.M608999200. View

20.

Sun X, Butterworth M, MacFarlane M, Dubiel W, Ciechanover A, Cohen G . Caspase activation inhibits proteasome function during apoptosis. Mol Cell. 2004; 14(1):81-93. DOI: 10.1016/s1097-2765(04)00156-x. View