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

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.