Trimming of ubiquitin chains by proteasome-associated deubiquitinating enzymes.
The proteasome generally recognizes substrate via its multiubiquitin chain followed by ATP-dependent unfolding and translocation of the substrate from the regulatory particle into the proteolytic core particle to be degraded. Substrate-bound ubiquitin groups are for the most part not delivered to the core particle and broken down together with substrate but instead recovered as intact free ubiquitin and ubiquitin chains. Substrate deubiquitination on the proteasome is mediated by three distinct deubiquitinating enzymes associated with the regulatory particle: RPN11, UCH37, and USP14. RPN11 cleaves at the base of the ubiquitin chain where it is linked to the substrate, whereas UCH37 and apparently USP14 mediate a stepwise removal of ubiquitin from the substrate by disassembling the chain from its distal tip. In contrast to UCH37 and USP14, RPN11 shows degradation-coupled activity; RPN11-mediated deubiquitination is apparently delayed until the proteasome is committed to degrade the substrate. Accordingly, RPN11-mediated deubiquitination promotes substrate degradation. In contrast, removal of ubiquitin prior to commitment could antagonize substrate degradation by promoting substrate dissociation from the proteasome. Emerging evidence suggests that USP14 and UCH37 can both suppress substrate degradation in this way. One line of study has shown that small molecule USP14 inhibitors can enhance proteasome function in cells, which is consistent with this model. Enhancing protein degradation could potentially have therapeutic applications for diseases involving toxic proteins that are proteasome substrates. However, the responsiveness of substrates to inhibition of proteasomal deubiquitinating enzymes may vary substantially. This substrate specificity and its mechanistic basis should be addressed in future studies.
Lee
Min Jae
MJ
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Lee
Byung-Hoon
BH
Hanna
John
J
King
Randall W
RW
Finley
Daniel
D
D000818:Animals; D002268:Carboxypeptidases / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D013379:Substrate Specificity; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors / Q000378:metabolism; D057149:Ubiquitinated Proteins / Q000378:metabolism*
D057149:Ubiquitinated Proteins; D002268:Carboxypeptidases; D010450:Endopeptidases; D043222:Ubiquitin Thiolesterase; D046988:Proteasome Endopeptidase Complex
Nat Chem Biol. 2009 Nov;5(11):815-22
19841631
Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):11907-12
19581590
Trends Biochem Sci. 2006 Dec;31(12):647-53
17074491
Nature. 2008 May 22;453(7194):548-52
18497827
Science. 2002 Oct 18;298(5593):611-5
12183636
Methods Enzymol. 2005;399:215-27
16338358
EMBO J. 2000 Jan 4;19(1):94-102
10619848
J Biol Chem. 2009 Dec 18;284(51):35485-94
19858201
Mol Cell Biol. 2003 Dec;23(24):9251-61
14645527
Dev Biol. 2009 Jan 1;325(1):33-42
18926813
Biochemistry. 1998 Mar 10;37(10):3358-68
9521656
Nature. 2002 Sep 26;419(6905):403-7
12353037
Nature. 1997 Feb 20;385(6618):737-40
9034192
Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):11943-7
19581588
Proc Natl Acad Sci U S A. 2010 Aug 3;107(31):13854-9
20634424
Annu Rev Biochem. 2009;78:363-97
19489724
Nat Cell Biol. 2006 Jul;8(7):700-10
16799550
Nat Cell Biol. 2006 Sep;8(9):994-1002
16906146
Free Radic Res. 2006 Dec;40(12):1250-8
17090414
Nature. 2010 Sep 9;467(7312):179-84
20829789
Recent Results Cancer Res. 2010;184:173-87
20072838
Mol Biol Cell. 2008 Mar;19(3):1072-82
18162577
Nature. 2008 May 22;453(7194):481-8
18497817
EMBO J. 2009 Mar 18;28(6):621-31
19214193
Mol Cell. 2009 Dec 11;36(5):794-804
20005843
Cell. 2007 May 18;129(4):747-59
17512408
Cell. 2006 Oct 6;127(1):99-111
17018280
Ann N Y Acad Sci. 1998 Jun 30;850:394-7
9668565
Biochim Biophys Acta. 1977 Sep 27;494(1):126-30
20153
Annu Rev Biochem. 2009;78:477-513
19489727