Autophagic Flux Is Regulated by Interaction Between the C-terminal Domain of PATCHED1 and ATG101.
Autophagic Flux Is Regulated by Interaction Between the C-terminal Domain of PATCHED1 and ATG101.
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DOI：
10.1158/1541-7786.mcr-17-0597
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发表时间：
2018-05
期刊：
影响因子：
--
通讯作者：
Riobo-Del Galdo NA
中科院分区：
文献类型：
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作者：
Chen X;Morales-Alcala CC;Riobo-Del Galdo NA
Hedgehog（Hh）受体Patched 1（PTCH 1）是一种众所周知的肿瘤抑制因子，其活性形式抑制Smoothened（SMO）活性，抑制增殖并诱导凋亡。胞质C-末端结构域（CTD）调节PTCH 1周转并使促凋亡复合物成核。在这项研究中，从机制上确定了自噬相关10（ATG 101），对哺乳动物自噬至关重要，与PTCH 1的CTD物理相互作用，并将其连接到ULK复合物，ULK复合物刺激自噬机制以响应营养物质可用性的变化。这种相互作用导致基础自噬通量的阻断和具有未降解货物的自噬体的积累。值得注意的是，PTCH 1的这种功能不依赖于其对SMO的抑制活性，如在SMO缺陷细胞中或在SMO抑制剂存在下所示，但与Sonic Hedgehog（SHH）相反。这些发现揭示了PTCH 1的一种新的非经典功能，该功能限制了由ATG 101介导的自噬，这可能对Hh依赖性癌症具有治疗意义。
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 pro-apoptotic complex. In this study, it was mechanistically determined that Autophagy Related 10 (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 non-canonical function of PTCH1 that limits autophagy, mediated by ATG101, which could have therapeutic implications in Hh-dependent cancers.