IGF2BP1/IMP1 deletion enhances a facultative stem cell state via regulation ofMAP1LC3B

Abstract

Homeostatic tissue maintenance requires coordinated regulation of metabolic processes including macroautophagy/autophagy. Autophagy dysregulation underlies numerous human diseases. Our prior work revealed that the RNA binding protein IGF2BP1/IMP1 binds transcripts encoding autophagy-related proteins. Furthermore, Imp1 deletion in gastrointestinal epithelial cells in mice was associated with enhanced autophagy flux and improved recovery from tissue injury. In the current study, we evaluated molecular mechanisms underlying IMP1 modulation of autophagy. We report increased expression of autophagy protein microtubule associated protein 1 light-chain 3B (MAP1LC3B) in cells with IMP1 deletion compared to control cells. MAP1LC3B expression was also increased in cells with mutated IMP1 phosphorylation sites. Luciferase reporter assays demonstrate increased translation of MAP1LC3B-3prime-UTR in cells with IMP1 deletion. Furthermore, we find that IMP1 co-localizes with MAP1LC3B transcripts at homeostasis, and co-localization is decreased in cells where IMP1 phosphorylation sites are mutated. IMP1 localization with MAP1LC3B transcripts is also decreased following cell stress. Taken together, our data support a model whereby IMP1 regulates MAP1LC3B translation which can serve as a mechanism to calibrate autophagy levels in the cell. This new mechanism may be particularly important in gastrointestinal epithelial cells, where autophagy is essential for tissue recovery following injury, or in diseases such as inflammatory bowel disease where defective autophagy is implicated.