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

Nat Commun. 2021 May 31;12(1):3258. doi: 10.1038/s41467-021-23539-5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Animals
  • Carcinogenesis / genetics*
  • Carcinogenesis / pathology
  • Cell Line, Tumor
  • Computer Simulation
  • DNA Mutational Analysis
  • Datasets as Topic
  • Gene Knockdown Techniques
  • Glycogen / metabolism
  • Humans
  • Kaplan-Meier Estimate
  • Macroautophagy / genetics*
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Microtubule-Associated Proteins / metabolism
  • Models, Genetic*
  • Muscle Proteins / genetics*
  • Muscle Proteins / metabolism
  • Mutation
  • Neoplasms / genetics*
  • Neoplasms / mortality
  • Neoplasms / pathology
  • Pentose Phosphate Pathway / genetics
  • Protein Interaction Domains and Motifs / genetics
  • Proteome / genetics
  • RNA-Seq
  • Tissue Array Analysis
  • Warburg Effect, Oncologic
  • Xenograft Model Antitumor Assays


  • MAP1LC3A protein, human
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Muscle Proteins
  • Proteome
  • Stbd1 protein, human
  • Glycogen