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Model-based analysis uncovers mutations altering autophagy selectivity in human cancer

Zhu Han, Weizhi Zhang, Wanshan Ning, Chenwei Wang, Wankun Deng, Zhidan Li, Zehua Shang, Xiaofei Shen, Xiaohui Liu, Otto Baba, Tsuyoshi Morita, Lu Chen, Yu Xue () and Da Jia ()
Additional contact information
Zhu Han: Sichuan University
Weizhi Zhang: Huazhong University of Science and Technology
Wanshan Ning: Huazhong University of Science and Technology
Chenwei Wang: Huazhong University of Science and Technology
Wankun Deng: Huazhong University of Science and Technology
Zhidan Li: Sichuan University
Zehua Shang: Sichuan University
Xiaofei Shen: Hospital of Chengdu University of Traditional Chinese Medicine
Xiaohui Liu: Tsinghua University
Otto Baba: Tokushima University Graduate School
Tsuyoshi Morita: Tokushima University Graduate School
Lu Chen: Sichuan University
Yu Xue: Huazhong University of Science and Technology
Da Jia: Sichuan University

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract Autophagy can selectively target protein aggregates, pathogens, and dysfunctional organelles for the lysosomal degradation. Aberrant regulation of autophagy promotes tumorigenesis, while it is far less clear whether and how tumor-specific alterations result in autophagic aberrance. To form a link between aberrant autophagy selectivity and human cancer, we establish a computational pipeline and prioritize 222 potential LIR (LC3-interacting region) motif-associated mutations (LAMs) in 148 proteins. We validate LAMs in multiple proteins including ATG4B, STBD1, EHMT2 and BRAF that impair their interactions with LC3 and autophagy activities. Using a combination of transcriptomic, metabolomic and additional experimental assays, we show that STBD1, a poorly-characterized protein, inhibits tumor growth via modulating glycogen autophagy, while a patient-derived W203C mutation on LIR abolishes its cancer inhibitory function. This work suggests that altered autophagy selectivity is a frequently-used mechanism by cancer cells to survive during various stresses, and provides a framework to discover additional autophagy-related pathways that influence carcinogenesis.

Date: 2021
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DOI: 10.1038/s41467-021-23539-5

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