부산대학교 도서관

Cells use noncanonical autophagy, also called conjugation of ATG8 to single membranes (CASM), to label damaged intracellular compartments with ubiquitin‐like ATG8 family proteins in order to signal danger caused by pathogens or toxic compounds. CASM relies on E3 complexes to sense membrane damage, but so far, only the mechanism to activate ATG16L1‐containing E3 complexes, associated with proton gradient loss, has been described. Here, we show that TECPR1‐containing E3 complexes are key mediators of CASM in cells treated with a variety of pharmacological drugs, including clinically relevant nanoparticles, transfection reagents, antihistamines, lysosomotropic compounds, and detergents. Interestingly, TECPR1 retains E3 activity when ATG16L1 CASM activity is obstructed by the Salmonella Typhimurium pathogenicity factor SopF. Mechanistically, TECPR1 is recruited by damage‐induced sphingomyelin (SM) exposure using two DysF domains, resulting in its activation and ATG8 lipidation. In vitro assays using purified human TECPR1‐ATG5‐ATG12 complex show direct activation of its E3 activity by SM, whereas SM has no effect on ATG16L1‐ATG5‐ATG12. We conclude that TECPR1 is a key activator of CASM downstream of SM exposure. Synopsis: TECPR1 utilizes its Dysferlin domains to detect cytosol‐exposed sphingomyelin at sites of membrane damage, which also triggers its E3 activity in CASM. Unlike ATG16L1, TECPR1 activity remains unaffected by the Salmonella Typhimurium factor SopF. TECPR1‐ATG5‐ATG12 is a key E3 complex in CASM response to membrane damage.TECPR1 is recruited by damage‐induced cytosolic sphingomyelin exposure.DysF domains of TECPR1 bind to sphingomyelin and activate its E3 activity.Inhibition of ATG16L1‐mediated CASM by the Salmonella Typhimurium factor SopF does not affect the E3 activity of TECPR1. [ABSTRACT FROM AUTHOR]