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

[wiskott-aldrich syndrome]

WASH (Wiskott-Aldrich syndrome protein (WASP ) and SCAR homolog ) was identified to function in endosomal sorting via Arp 2 /3 activation . We previously demonstrated that WASH is a new interactor of BECN 1 and present in the BECN 1 -PIK 3 C 3 complex with AMBRA 1 . The AMBRA 1 -DDB 1 -CUL 4 A complex is an E 3 ligase for K 63 -linked ubiquitination of BECN 1 , which is required for starvation-induced autophagy . WASH suppresses autophagy by inhibition of BECN 1 ubiquitination . However , how AMBRA 1 is regulated during autophagy remains elusive . Here , we found that RNF 2 associates with AMBRA 1 to act as an E 3 ligase to ubiquitinate AMBRA 1 via K 48 linkage . RNF 2 mediates ubiquitination of AMBRA 1 at lysine 45 . Notably , RNF 2 deficiency enhances autophagy induction . Upon autophagy induction , RNF 2 potentiates AMBRA 1 degradation with the help of WASH . WASH deficiency impairs the association of RNF 2 with AMBRA 1 to impede AMBRA 1 degradation . Our findings reveal another novel layer of regulation of autophagy through WASH recruitment of RNF 2 for AMBRA 1 degradation leading to downregulation of autophagy .

Diseases
Validation

Diseases presenting "deficiency impairs" symptom

adrenomyeloneuropathy

pyruvate dehydrogenase deficiency

wiskott-aldrich syndrome

x-linked adrenoleukodystrophy

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