NOXA, a sensor of proteasome integrity, is degraded by 26S proteasomes by an ubiquitin-independent pathway that is blocked by MCL-1

A. Craxton, M. Butterworth, N. Harper, L. Fairall, J. Schwabe, Aaron Ciechanover, G. M. Cohen

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Ubiquitin (Ub)-mediated proteasome-dependent proteolysis is critical in regulating multiple biological processes including apoptosis. We show that the unstructured BH3-only protein, NOXA, is degraded by an Ub-independent mechanism requiring 19S regulatory particle (RP) subunits of the 26S proteasome, highlighting the possibility that other unstructured proteins reported to be degraded by 20S proteasomes in vitro may be bona fide 26S proteasome substrates in vivo. A lysine-less NOXA (NOXA-LL) mutant, which is not ubiquitinated, is degraded at a similar rate to wild-type NOXA. Myeloid cell leukemia 1, but not other anti-apoptotic BCL-2 family proteins, stabilizes NOXA by interaction with the NOXA BH3 domain. Depletion of 19S RP subunits, but not alternate proteasome activator REG subunits, increases NOXA half-life in vivo. A NOXA-LL mutant, which is not ubiquitinated, also requires an intact 26S proteasome for degradation. Depletion of the 19S non-ATPase subunit, PSMD1 induces NOXA-dependent apoptosis. Thus, disruption of 26S proteasome function by various mechanisms triggers the rapid accumulation of NOXA and subsequent cell death strongly implicating NOXA as a sensor of 26S proteasome integrity.

Original languageEnglish
Pages (from-to)1424-1434
Number of pages11
JournalCell Death and Differentiation
Volume19
Issue number9
DOIs
StatePublished - 1 Sep 2012

Fingerprint

Proteasome Endopeptidase Complex
Ubiquitin
Intrinsically Disordered Proteins
Apoptosis
Biological Phenomena
Myeloid Leukemia
Myeloid Cells
Proteolysis
Lysine
Half-Life
Proteins
Cell Death
ATP dependent 26S protease

Keywords

  • MCL-1
  • NOXA
  • apoptosis
  • proteasome
  • ubiquitin

Cite this

Craxton, A. ; Butterworth, M. ; Harper, N. ; Fairall, L. ; Schwabe, J. ; Ciechanover, Aaron ; Cohen, G. M. / NOXA, a sensor of proteasome integrity, is degraded by 26S proteasomes by an ubiquitin-independent pathway that is blocked by MCL-1. In: Cell Death and Differentiation. 2012 ; Vol. 19, No. 9. pp. 1424-1434.
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NOXA, a sensor of proteasome integrity, is degraded by 26S proteasomes by an ubiquitin-independent pathway that is blocked by MCL-1. / Craxton, A.; Butterworth, M.; Harper, N.; Fairall, L.; Schwabe, J.; Ciechanover, Aaron; Cohen, G. M.

In: Cell Death and Differentiation, Vol. 19, No. 9, 01.09.2012, p. 1424-1434.

Research output: Contribution to journalArticle

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