iCAL: a new pipeline to investigate autophagy selectivity and cancer
iCAL: a new pipeline to investigate autophagy selectivity and cancer
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iCAL：研究自噬选择性和癌症的新途径
DOI：
10.1080/15548627.2021.1939972
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发表时间：
2021-06
期刊：
影响因子：
13.3
通讯作者：
Jia Da
中科院分区：
文献类型：
--
作者：
Zhang Weizhi;Han Zhu;Xue Yu;Jia Da
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物质。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，并导致人类疾病，如癌症。为了探索异常自噬选择性与人类癌症之间的联系，我们开发了一种称为“癌症相关LC 3相互作用区域蛋白质的推断”（iCAL）的管道，该管道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，我们已经在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ATG 4 B，STBD 1，EHMT 2和BRAF中的LAM会损害它们与LC 3和/或自噬活性的相互作用。此外，我们发现STBD 1是一种以前表征不佳的蛋白质，通过癌细胞中的代谢重编程抑制肿瘤生长。STBD 1（W203 C）中的患者源性突变破坏了与LC 3的相互作用并促进肿瘤生长。总之，iCAL提供了一个令人兴奋的新途径，发现新的自噬途径，有助于致癌。
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.
基于模型的分析揭示了改变人类癌症自噬选择性的突变
影响因子：
16.6
作者：
Han Z;Zhang W;Ning W;Wang C;Deng W;Li Z;Shang Z;Shen X;Liu X;Baba O;Morita T;Chen L;Xue Y;Jia D
通讯作者：
Jia D