ABSTRACT

Macroautophagy/autophagy can selectively degrade misfolded proteins, damaged organelles and other cargoes. It is conceivable that alteration of the degradation processes could disrupt normal cellular signaling and contribute to human diseases such as cancer. To explore the link between aberrant autophagy selectivity and human cancer, we have developed a pipeline called “inference of cancer-associated LC3-interacting region-containing proteins” (iCAL), which integrates a sequence-based predictor, a model-based computational method, publicly available cancer mutations, and multiple experimental approaches. Using iCAL, we have identified 222 LIR motif-associated mutations (LAMs) in 148 LIR-containing proteins (LIRCPs), and validated that LAMs in ATG4B, STBD1, EHMT2 and BRAF impair their interactions with LC3 and/or autophagy activities. Moreover, we uncovered that STBD1, a previously poorly-characterized protein, inhibits tumor growth via metabolism reprogramming in cancer cells. A patient-derived mutation in STBD1 (W203C) disrupts the interaction with LC3 and promotes tumor growth. Taken together, iCAL provides an exciting new avenue to discover novel autophagy pathways that contribute to carcinogenesis.

摘要

巨自噬/自噬可以选择性地降解错误折叠的蛋白质、受损的细胞器和其他货物。可以想象，降解过程的改变可能会破坏正常的细胞信号传导并导致癌症等人类疾病。为了探索异常自噬选择性与人类癌症之间的联系，我们开发了一条名为“癌症相关L 的推断”的管道。包含 C3 相互作用区域的蛋白质”（iCAL），它集成了基于序列的预测器、基于模型的计算方法、公开可用的癌症突变和多种实验方法。使用 iCAL，我们在 148 个含 LIR 的蛋白质 (LIRCP) 中鉴定了 222 个 LIR 基序相关突变 (LAM)，并验证了 ATG4B、STBD1、EHMT2 和 BRAF 中的 LAM 会损害它们与 LC3 和/或自噬活性的相互作用。此外，我们还发现 STBD1 是一种先前表征不佳的蛋白质，它通过癌细胞中的代谢重编程来抑制肿瘤生长。STBD1 (W203C) 中源自患者的突变破坏了与 LC3 的相互作用并促进了肿瘤生长。总之，iCAL 提供了一个令人兴奋的新途径来发现导致致癌作用的新型自噬途径。