iCAL: a new pipeline to investigate autophagy selectivity and cancer

Area of Science:

• Cell Biology
• Molecular Oncology
• Biochemistry

Background:

• Macroautophagy/autophagy is a cellular process for degrading damaged components.
• Dysregulation of autophagy selectivity is implicated in human diseases, including cancer.
• Understanding the link between autophagy and cancer is crucial for therapeutic development.

Purpose of the Study:

• To investigate the connection between aberrant autophagy selectivity and human cancer.
• To develop a computational pipeline (iCAL) for identifying cancer-associated mutations in autophagy-related proteins.
• To discover novel autophagy pathways involved in carcinogenesis.

Main Methods:

• Developed the 'inference of cancer-associated LC3-interacting region-containing proteins' (iCAL) pipeline.
• Integrated sequence-based prediction, computational modeling, and experimental validation.
• Analyzed publicly available cancer mutation data and experimental approaches.

Main Results:

• Identified 222 LIR motif-associated mutations (LAMs) in 148 LIR-containing proteins (LIRCPs).
• Validated that LAMs in ATG4B, STBD1, EHMT2, and BRAF impair LC3 interactions and/or autophagy.
• Discovered STBD1 inhibits tumor growth via metabolic reprogramming; a patient mutation (W203C) promotes tumor growth by disrupting LC3 interaction.

Conclusions:

• The iCAL pipeline is a novel tool for discovering autophagy-related proteins and mutations in cancer.
• Aberrant autophagy selectivity, driven by specific mutations, contributes to cancer development.
• STBD1 plays a significant role in tumor suppression through metabolic reprogramming, offering potential therapeutic targets.