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Clusterin facilitates stress-induced lipidation of LC3 and autophagosome biogenesis to enhance cancer cell survival

Fan Zhang,M. Kumano,E. Beraldi,L. Fazli,C. Du,Susan Moore,P. Sorensen,A. Zoubeidi,M. Gleave

Published 2014 in Nature Communications

ABSTRACT

We define stress-induced adaptive survival pathways linking autophagy with the molecular chaperone clusterin (CLU) that function to promote anticancer treatment resistance. During treatment stress, CLU co-localizes with LC3 via an LIR-binding sequence within autophagosome membranes, functioning to facilitate LC3–Atg3 heterocomplex stability and LC3 lipidation, and thereby enhance autophagosome biogenesis and autophagy activation. Stress-induced autophagy is attenuated with CLU silencing in CLU−/− mice and human prostate cancer cells. CLU-enhanced cell survival occurs via autophagy-dependent pathways, and is reduced following autophagy inhibition. Combining CLU inhibition with anticancer treatments attenuates autophagy activation, increases apoptosis and reduces prostate cancer growth. This study defines a novel adaptor protein function for CLU under stress conditions, and highlights how co-targeting CLU and autophagy can amplify proteotoxic stress to delay cancer progression. The induction of autophagy under stress conditions such as chemotherapy is a contributing factor towards resistance to anticancer therapy. Here, Zhang et al. identify the molecular chaperone clusterin as an adaptor that facilitates lipidation of LC3 and autophagosome biogenesis.

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