RNF2 is recruited by WASH to ubiquitinate AMBRA1 leading to downregulation of autophagy

WASH （Wiskott-Aldrich syndrome protein （WASP） and SCAR homolog） was identified to function in endosomal sorting via Arp2/3 activation. We previously demonstrated that WASH is a new interactor of BECN1 and present in the BECN1-PIK3C3 complex with AMBRA1. The AMBRA1-DDB1-CUL4A complex is an E3 ligase...

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Bibliographic Details
Published in:Cell research 2014-08, Vol.24 (8), p.943-958
Main Authors: Xia, Pengyan, Wang, Shuo, Huang, Guanling, Du, Ying, Zhu, Pingping, Li, Man, Fan, Zusen
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - antagonists & inhibitors
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - metabolism
Animals
Apoptosis Regulatory Proteins - metabolism
Autophagy
Beclin-1
Cell Line
Down-Regulation
Mice
Mice, Knockout
Microfilament Proteins - metabolism
Original
Phosphatidylinositol 3-Kinases - chemistry
Phosphatidylinositol 3-Kinases - metabolism
Polycomb Repressive Complex 1 - genetics
Polycomb Repressive Complex 1 - metabolism
RNA Interference
RNA, Small Interfering - metabolism
SCAR
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
Ubiquitination
Vesicular Transport Proteins - metabolism
WASP
同源物
泛素化
综合征
自噬
连接酶
配合物
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Summary:WASH （Wiskott-Aldrich syndrome protein （WASP） and SCAR homolog） was identified to function in endosomal sorting via Arp2/3 activation. We previously demonstrated that WASH is a new interactor of BECN1 and present in the BECN1-PIK3C3 complex with AMBRA1. The AMBRA1-DDB1-CUL4A complex is an E3 ligase for K63-1inked ubiquitination of BECN1, which is required for starvation-induced autophagy. WASH suppresses autophagy by inhibition of BECN1 ubiquitination. However, how AMBRA1 is regulated during autophagy remains elusive. Here, we found that RNF2 associates with AMBRA1 to act as an E3 ligase to ubiquitinate AMBRA1 via K48 linkage. RNF2 mediates ubiquitination of AMBRA1 at lysine 45. Notably, RNF2 deficiency enhances autophagy induction. Upon autophagy induction, RNF2 potentiates AMBRA1 degradation with the help of WASH. WASH deficiency impairs the association of RNF2 with AMBRA1 to impede AMBRA1 degradation. Our findings reveal another novel layer of regulation of autophagy through WASH recruitment of RNF2 for AMBRA1 degradation leading to downregulation of autophagy.
ISSN:1001-0602
1748-7838
DOI:10.1038/cr.2014.85