TY - JOUR
T1 - Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis
AU - Zhong, Qing
AU - Gao, Wenhua
AU - Du, Fenghe
AU - Wang, Xiaodong
N1 - Funding Information:
We thank Dr. Zhijian Chen for E1 recombinant protein and E2 expression vectors, Dr. Wayne Lai for generation of monoclonal antibody against Mule, Dr. Nikolai Grishine and Dr. Phang-Lang Chen for helpful discussion, and Dr. Eileen White for critical reading of this manuscript. Suspension-cultured HeLa cells were obtained from the Cell Culture Center in Minneapolis, Minnesota. X.W. is also supported by grants from NIH (GMRO1-57158) and the Welch Foundation (I-1412).
PY - 2005/7/1
Y1 - 2005/7/1
N2 - The elimination of Mcl-1, an anti-apoptotic Bcl-2 family member, is an early and required step for DNA damage-induced apoptosis. The degradation of Mcl-1 can be blocked by proteasome inhibitors, suggesting a role for the ubiquitin proteasome pathway in apoptosis. Here, we demonstrate that Mcl-1 is ubiquinated at five lysines. Biochemical fractionation of cell extracts allowed us to identify a 482 kDa HECT-domain-containing ubiquitin ligase named Mule (Mcl-1 ubiquitin ligase E3) that is both required and sufficient for the polyubiquitination of Mcl-1. Mule also contains a region similar to the Bcl-2 homology region 3 (BH3) domain that allows Mule to specifically interact with Mcl-1. Elimination of Mule expression by RNA interference stabilizes Mcl-1 protein, resulting in an attenuation of the apoptosis induced by DNA-damage agents. Thus, Mule is a unique BH3-containing E3 ubiquitin ligase apical to Bcl-2 family proteins during DNA damage-induced apoptosis.
AB - The elimination of Mcl-1, an anti-apoptotic Bcl-2 family member, is an early and required step for DNA damage-induced apoptosis. The degradation of Mcl-1 can be blocked by proteasome inhibitors, suggesting a role for the ubiquitin proteasome pathway in apoptosis. Here, we demonstrate that Mcl-1 is ubiquinated at five lysines. Biochemical fractionation of cell extracts allowed us to identify a 482 kDa HECT-domain-containing ubiquitin ligase named Mule (Mcl-1 ubiquitin ligase E3) that is both required and sufficient for the polyubiquitination of Mcl-1. Mule also contains a region similar to the Bcl-2 homology region 3 (BH3) domain that allows Mule to specifically interact with Mcl-1. Elimination of Mule expression by RNA interference stabilizes Mcl-1 protein, resulting in an attenuation of the apoptosis induced by DNA-damage agents. Thus, Mule is a unique BH3-containing E3 ubiquitin ligase apical to Bcl-2 family proteins during DNA damage-induced apoptosis.
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U2 - 10.1016/j.cell.2005.06.009
DO - 10.1016/j.cell.2005.06.009
M3 - Article
C2 - 15989957
AN - SCOPUS:21244472965
SN - 0092-8674
VL - 121
SP - 1085
EP - 1095
JO - Cell
JF - Cell
IS - 7
ER -