Post-transcriptional regulation of intestinal epithelial cell repair by RNA binding protein IMP1.

Chatterji P, Whelan KA, Andres SF, Samper FC, Simon LA, Mizuno R, Lundsmith ET, Lee DSM, Liang S, Wijeratne HRS, Marti S, Chau L, Williams PA, Giroux V, Wilkins BJ, Wu GD, Shah P, Tartaglia GG, Hamilton KE

bioRxiv :

2018

Abstract

RNA binding proteins, such as IMP1, are emerging as essential regulators of intestinal development and cancer. IMP1 hypomorphic mice exhibit severe intestinal growth defects, yet it's role in adult intestinal epithelium is unclear. We employed ribosome profiling to test the effect of IMP1 loss on the "translatome" in colon cancer cell lines. In parallel, we evaluated mice with intestinal epithelial-specific Imp1 deletion (Imp1 Δ\DeltaIEC) following irradiation or colitis models. Ribosome-profiling revealed translation efficiency changes for multiple pathways important for intestinal homeostasis, including autophagy, in IMP1 knockout cells. We found increased autophagy flux in Imp1 Δ\DeltaIEC mice, reinforced through in silico and biochemical analyses revealing direct binding of IMP1 to autophagy transcripts MAP1LC3B and ATG3. We found that Imp1 Δ\DeltaIEC mice exhibit enhanced recovery following irradiation, which is attenuated with genetic deletion of autophagy gene Atg7. Finally, we demonstrated that IMP1 is upregulated in Crohn's disease patients and Imp1 loss lessened colitis severity in mice. These studies demonstrate that IMP1 acts as a posttranscriptional regulator of gut epithelial repair post-irradiation and colitis, in part through modulation of autophagy.