LAUSR

The Hedgehog (Hh) receptor Patched1 (PTCH1) is a well-known tumor suppressor that in its active form represses Smoothened (SMO) activity, inhibits proliferation, and induces apoptosis. The cytoplasmic C-terminal domain (CTD) regulates PTCH1 turnover and nucleates a proapoptotic complex. In this study, it was mechanistically determined that Autophagy-related 101 (ATG101), essential for mammalian autophagy, physically interacts with the CTD of PTCH1 and connects it to the ULK complex, which stimulates the autophagy machinery in response to changes in nutrient availability. This interaction results in a blockade of basal autophagic flux and accumulation of autophagosomes with undegraded cargo. Remarkably, this function of PTCH1 is independent of its repressive activity on SMO, as shown in SMO-deficient cells or in the presence of a SMO inhibitor, but is opposed by Sonic Hedgehog (SHH). These findings reveal a novel noncanonical function of PTCH1 that limits autophagy, mediated by ATG101, which could have therapeutic implications in Hh-dependent cancers. Implications: Loss-of-function of the tumor suppressor Patched1 might promote cancer cell fitness by increasing autophagic flux in response to metabolic or environmental stresses. Mol Cancer Res; 16(5); 909–19. ©2018 AACR.