Autophagy gene expression profiling identifies a defective microtubule-associated protein light chain 3A mutant in cancer

Abstract

The cellular stress response autophagy has been implicated in various diseases including neuro-degeneration and cancer. The role of autophagy in cancer is not clearly understood and both tumour promoting and tumour suppressive effects of autophagy have been reported, which complicates the design of therapeutic strategies based on targeting the autophagy pathway. Here, we have systematically analyzed gene expression data for 47 autophagy genes for deletions, amplifications and mutations in various cancers. We found that several cancer types have frequent autophagy gene amplifications, whereas deletions are more frequent in prostate adenocarcinomas. Other cancer types such as glioblastoma and thyroid carcinoma show very few alterations in any of the 47 autophagy genes. Overall, individual autophagy core genes are altered at low frequency in cancer, suggesting that cancer cells require functional autophagy. Some autophagy genes show frequent single base mutations, such as members of the ULK family of protein kinases. Furthermore, we found hotspot mutations in the arginine-rich stretch in MAP1LC3A resulting in reduced cleavage of MAP1LC3A by ATG4B both in vitro and in vivo, suggesting a functional implication of this gene mutation in cancer development.

A cancer associated somatic mutation in LC3B attenuates its binding to E1-like ATG7 protein and subsequent lipidation

“…Statistical significance determined by the two-tailed unpaired Student's t-test, using Holm-Sidak correction, *P < 0.05; **P < 0.01. mutations in autophagy genes in human cancer patient samples, the most frequent gene mutations are in autophagy regulators and pathway interactors, rather than mutations in the core machinery of autophagy [22,23]. Among the few reports on the latter group is a cancer-associated mutation in MAP1LC3A [24], which results in the protein's reduced cleavage by ATG4B and reduced autophagy levels. Our computational analysis shown here confirmed that mutations in core-machinery autophagy genes are indeed rare in different types of cancer.…”

The conformational and mutational landscape of the ubiquitin-like marker for the autophagosome formation in cancer

“…We then searched in literature for experimental data that could validate our predictions, and we found results in agreement with the functional impact for mutations at R70, D19, G120, and K49, supporting our results. Mutations at R70 showed no accumulation of the pro-forms for LC3B (Liu et al, 2013), slower kinetics for Atg4B-mediated cleavage (Costa et al, 2016) and reduced binding for more that 20 interactors (Behrends et al, 2010;Kraft et al, 2014;Olsvik et al, 2015). G120 is fundamental for a proper C-terminal cleavage, which is impaired when this glycine is mutated to alanine (Tanida et al, 2004) and also G120 substitution with alanine has been shown to impair the binding of lamin B1 with LC3B (Dou et al, 2015).…”

LC3C-Mediated Autophagy Selectively Regulates the Met RTK and HGF-Stimulated Migration and Invasion

“…Instead, Met/LC3C complex formation requires both the LC3C C-terminal tail and residue R76 located within the ubiquitin-like domain of LC3C, and LC3C mutants lacking either of these cannot restore autophagy-dependent Met loss in LC3Cdepleted cells. Although LC3C interactions involving R76 have not previously been explored, mutations at this residue occur in human cancers (Costa et al, 2016). Although R76 is conserved in hATG8 proteins and large-scale proteomics analysis of the autophagy network identified that a portion of LC3B interactions are dependent on this residue (Behrends et al, 2010), LC3B does not engage with Met, highlighting that this residue alone is not sufficient.…”