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

Zhu Han1, Weizhi Zhang2, Wanshan Ning2

  • 1Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China.

Nature Communications
|June 1, 2021
PubMed

Insights

This study identifies mutations affecting autophagy selectivity (LAMs) in cancer. A specific mutation in STBD1 impairs its tumor-suppressive function by disrupting glycogen autophagy.

Area of Science:

  • Cellular Biology
  • Molecular Oncology
  • Biochemistry

Background:

  • Autophagy regulates cellular homeostasis by degrading damaged components.
  • Aberrant autophagy is linked to cancer development, but tumor-specific alterations remain unclear.
  • Understanding autophagy's role in cancer is crucial for therapeutic strategies.

Purpose of the Study:

  • To investigate the link between altered autophagy selectivity and human cancer.
  • To identify and validate mutations impacting autophagy-related protein interactions.
  • To elucidate the function of STBD1 in tumor suppression via autophagy.

Main Methods:

  • Development of a computational pipeline to identify LIR motif-associated mutations (LAMs).
  • Validation of identified LAMs in proteins such as ATG4B, STBD1, EHMT2, and BRAF.
  • Integration of transcriptomic, metabolomic, and experimental assays to study STBD1 function.

Main Results:

  • Prioritized 222 potential LAMs in 148 proteins, linking autophagy selectivity to cancer.
  • Validated that LAMs impair protein interactions with LC3 and affect autophagy.
  • Demonstrated that STBD1 inhibits tumor growth via glycogen autophagy, and a patient-derived mutation abolishes this function.

Conclusions:

  • Altered autophagy selectivity is a common mechanism for cancer cell survival under stress.
  • Provides a framework for discovering novel autophagy-related pathways in carcinogenesis.
  • Highlights the importance of STBD1 and its LIR motif in cancer suppression.

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