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Model-based analysis uncovers mutations altering autophagy selectivity in human cancer
- Source :
- Nature Communications, Nature Communications, Vol 12, Iss 1, Pp 1-18 (2021)
- Publication Year :
- 2021
- Publisher :
- Nature Publishing Group UK, 2021.
-
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.<br />Although autophagy has been linked to tumourigenesis, it is unclear how genomic alterations affect autophagy selectivity in tumours. Here, the authors establish a pipeline that integrates computational and experimental approaches to show that altered autophagy selectivity is frequent in cancer cells and link glycogen autophagy with tumourigenesis.
- Subjects :
- 0301 basic medicine
Science
General Physics and Astronomy
Biology
medicine.disease_cause
General Biochemistry, Genetics and Molecular Biology
Article
Transcriptome
EHMT2
03 medical and health sciences
0302 clinical medicine
Histocompatibility Antigens
Neoplasms
Macroautophagy
medicine
Autophagy
Humans
Data mining
Mutation
Multidisciplinary
Cancer
General Chemistry
Autophagy-Related Protein 8 Family
Histone-Lysine N-Methyltransferase
medicine.disease
Warburg effect
Cancer metabolism
Cell biology
030104 developmental biology
Cancer cell
Carcinogenesis
Microtubule-Associated Proteins
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 12
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....4d053decd5d0d57ac1ccb193aee70458