The novel role of Sav1 in aggresome formation

Abstract

Intracellular deposition of misfolded protein aggregates into ubiquitin‐rich cytoplasmic inclusions is linked to the pathogenesis of many diseases. Recent genetic screens of fly mutants and molecular analysis have revealed that the Hippo/Salvador/Warts pathway controls both cell proliferation and cell death. Specifically, adaptor protein Salvador is the key component of this pathway. Using proteomics screening, we identified the molecular chaperone Hsp70 as a novel protein associated with Sav1 (mammalian homologue of Salvador). Sav1 targets to the aggresome and its sequestration to the aggresome is enhanced by the proteasome inhibitor MG132. Furthermore, Sav1 co‐localizes with Hsp70 and CHIP (carboxy terminus of Hsp70‐interacting protein) that has been shown to mediate substrate ubiquitination and degradation by the proteasome. This study suggests that Sav1 has a previously unexpected critical role in the aggresome pathway.