Volume 24, No 8, Aug 2014
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 24 Issue 8, August 2014: 943-958 | Open Access
ORIGINAL ARTICLES
RNF2 is recruited by WASH to ubiquitinate AMBRA1 leading to downregulation of autophagy
Pengyan Xia1,2,*, Shuo Wang1,*, Guanling Huang1,2, Ying Du1, Pingping Zhu1, Man Li1,2 and Zusen Fan1
1Key Laboratory of Infection and Immunity of CAS, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
2University of Chinese Academy of Sciences, Beijing 100049, China
Correspondence: Zusen Fan, Tel: 86-10-64888457; Fax: 86-10-64871293(fanz@moon.ibp.ac.cn)
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-linked 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.
10.1038/cr.2014.85
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