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

Abstract	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.
Authors	Pengyan Xia, Shuo Wang, Guanling Huang, Ying Du, Pingping Zhu, Man Li, Zusen Fan
Journal	Cell research (Cell Res) Vol. 24 Issue 8 Pg. 943-58 (Aug 2014) ISSN: 1748-7838 [Electronic] England
PMID	24980959 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Adaptor Proteins, Signal Transducing Ambra1 protein, mouse Apoptosis Regulatory Proteins Beclin-1 Becn1 protein, mouse Microfilament Proteins RNA, Small Interfering Vesicular Transport Proteins WASH protein, mouse Polycomb Repressive Complex 1 Rnf2 protein, mouse Ubiquitin-Protein Ligases Phosphatidylinositol 3-Kinases
Topics	Adaptor Proteins, Signal Transducing (antagonists & inhibitors, genetics, metabolism) Animals Apoptosis Regulatory Proteins (metabolism) Autophagy Beclin-1 Cell Line Down-Regulation Mice Mice, Knockout Microfilament Proteins (metabolism) Phosphatidylinositol 3-Kinases (chemistry, metabolism) Polycomb Repressive Complex 1 (genetics, metabolism) RNA Interference RNA, Small Interfering (metabolism) Ubiquitin-Protein Ligases (genetics, metabolism) Ubiquitination Vesicular Transport Proteins (metabolism)

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