UBXD7 binds multiple ubiquitin ligases and implicates p97 in HIF1 alpha turnover

TY - JOUR

T1 - UBXD7 binds multiple ubiquitin ligases and implicates p97 in HIF1 alpha turnover

A1 - Alexandru,Gabriela

A1 - Graumann,Johannes

A1 - Smith,Geoffrey T.

A1 - Kolawa,Natalie J.

A1 - Fang,Ruihua

A1 - Deshaies,Raymond J.

AU - Alexandru,Gabriela

AU - Graumann,Johannes

AU - Smith,Geoffrey T.

AU - Kolawa,Natalie J.

AU - Fang,Ruihua

AU - Deshaies,Raymond J.

PY - 2008/9/5

Y1 - 2008/9/5

N2 - <p>p97 is an ATP-dependent chaperone that plays an important role in endoplasmic reticulum-associated degradation but whose connections to turnover of soluble proteins remain sparse. Binding of p97 to substrates is mediated by cofactors that contain ubiquitin-binding domains. We employed "network proteomics'' to show that p97 assembles with all of the 13 mammalian UBX-domain proteins. The UBX proteins that bind ubiquitin conjugates also interact with dozens of E3 ubiquitin ligases, only one of which had been previously linked to p97. In particular, UBXD7 links p97 to the ubiquitin ligase CUL2/VHL and its substrate hypoxia-inducible factor 1 alpha (HIF1 alpha). Depletion of p97 leads to accumulation of endogenous HIF1 alpha and increased expression of a HIF1 alpha target gene. The large number of ubiquitin ligases found associated with UBX proteins suggests that p97 plays a far broader role than previously anticipated in the global regulation of protein turnover.</p>

AB - <p>p97 is an ATP-dependent chaperone that plays an important role in endoplasmic reticulum-associated degradation but whose connections to turnover of soluble proteins remain sparse. Binding of p97 to substrates is mediated by cofactors that contain ubiquitin-binding domains. We employed "network proteomics'' to show that p97 assembles with all of the 13 mammalian UBX-domain proteins. The UBX proteins that bind ubiquitin conjugates also interact with dozens of E3 ubiquitin ligases, only one of which had been previously linked to p97. In particular, UBXD7 links p97 to the ubiquitin ligase CUL2/VHL and its substrate hypoxia-inducible factor 1 alpha (HIF1 alpha). Depletion of p97 leads to accumulation of endogenous HIF1 alpha and increased expression of a HIF1 alpha target gene. The large number of ubiquitin ligases found associated with UBX proteins suggests that p97 plays a far broader role than previously anticipated in the global regulation of protein turnover.</p>

KW - AAA-ATPASE CDC48/P97

KW - RETICULUM-ASSOCIATED DEGRADATION

KW - VALOSIN-CONTAINING PROTEIN

KW - POLYUBIQUITIN CHAINS

KW - TRANSCRIPTION FACTOR

KW - SELECTIVE CHAPERONE

KW - MEMBRANE-FUSION

KW - 26S PROTEASOME

KW - ER

KW - COMPLEX

U2 - 10.1016/j.cell.2008.06.048

DO - 10.1016/j.cell.2008.06.048

M1 - Article

JO - Cell

JF - Cell

SN - 0092-8674

IS - 5

VL - 134

SP - 804

EP - 816

ER -