Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital of Sichuan University, Chengdu, China.
Department of Medical Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu, China.
Cell Death Dis. 2022 Jul 15;13(7):615. doi: 10.1038/s41419-022-05061-8.
Aggresome formation is a protective cellular response to counteract proteasome dysfunction by sequestering misfolded proteins and reducing proteotoxic stress. Autophagic degradation of the protein aggregates is considered to be a key compensating mechanism for balancing proteostasis. However, the precise role of autophagy in proteasome inhibition-induced aggresome biogenesis remains unclear. Herein, we demonstrate that in the early stage of proteasome inhibition, the maturation of the autophagosome is suppressed, which facilitates aggresome formation of misfolded proteins. Proteasome inhibition-induced phosphorylation of SQSTM1 T269/S272 inhibits its autophagic receptor activity and promotes aggresome formation of misfolded proteins. Inhibiting SQSTM1 T269/S272 phosphorylation using Doramapimod aggravates proteasome inhibitor-mediated cell damage and tumor suppression. Taken together, our data reveal a negative effect of autophagy on aggresome biogenesis and cell damage upon proteasome inhibition. Our study suggests a novel therapeutic intervention for proteasome inhibitor-mediated tumor treatment.
聚集物形成是一种保护性的细胞反应，通过隔离错误折叠的蛋白质和减少蛋白毒性应激来对抗蛋白酶体功能障碍。自噬性降解蛋白聚集体被认为是平衡蛋白稳态的关键补偿机制。然而，自噬在蛋白酶体抑制诱导的聚集物生物发生中的精确作用仍不清楚。本文中，我们证明在蛋白酶体抑制的早期阶段，自噬体的成熟被抑制，从而促进错误折叠蛋白的聚集物形成。蛋白酶体抑制诱导的 SQSTM1 T269/S272 磷酸化抑制其自噬受体活性并促进错误折叠蛋白的聚集物形成。使用 Doramapimod 抑制 SQSTM1 T269/S272 的磷酸化会加剧蛋白酶体抑制剂介导的细胞损伤和肿瘤抑制。总之，我们的数据揭示了自噬对蛋白酶体抑制诱导的聚集物生物发生和细胞损伤的负向影响。我们的研究为蛋白酶体抑制剂介导的肿瘤治疗提供了一种新的治疗干预策略。
