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. 2021 Sep;191(9):1537-1549.
doi: 10.1016/j.ajpath.2021.06.004. Epub 2021 Jun 15.

Rictor/Mammalian Target of Rapamycin Complex 2 Signaling Protects Colonocytes from Apoptosis and Prevents Epithelial Barrier Breakdown

Felipe Castro-Martinez  1 , Aurora Candelario-Martinez  1 , Maria R Encarnacion-Garcia  1 , Zayda Piedra-Quintero  2 , Raul Bonilla-Moreno  2 , Abigail Betanzos  3 , Rocio Perez-Orozco  4 , Maria A Hernandez-Cueto  5 , Jose E Muñoz-Medina  5 , Genaro Patiño-Lopez  6 , Michael Schnoor  2 , Nicolas Villegas-Sepulveda  7 , Porfirio Nava  8
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Free article

Rictor/Mammalian Target of Rapamycin Complex 2 Signaling Protects Colonocytes from Apoptosis and Prevents Epithelial Barrier Breakdown

Felipe Castro-Martinez et al. Am J Pathol. 2021 Sep.
Free article

Abstract

Epithelial barrier impairment is a hallmark of several pathologic processes in the gut, including inflammatory bowel diseases. Several intracellular signals prevent apoptosis in intestinal epithelial cells. Herein, we show that in colonocytes, rictor/mammalian target of rapamycin complex 2 (mTORC2) signaling is a prosurvival stimulus. Mechanistically, mTORC2 activates Akt, which, in turn, inhibits apoptosis by phosphorylating B-cell lymphoma 2 (BCL2) associated agonist of cell death (Bad) and preventing caspase-3 activation. Nevertheless, during inflammation, rictor/mTORC2 signaling declines and Akt activity is reduced. Consequently, active caspase-3 increases in surface colonocytes undergoing apoptosis/anoikis and causes epithelial barrier breakdown. Likewise, Rictor ablation in intestinal epithelial cells interrupts mTORC2/Akt signaling and increases apoptosis/anoikis of surface colonocytes without affecting the crypt architecture. The increase in epithelial permeability induced by Rictor ablation produces a mild inflammatory response in the colonic mucosa, but minimally affects the development/establishment of colitis. The data identify a previously unknown mechanism by which rictor/mTORC2 signaling regulates apoptosis/anoikis in intestinal epithelial cells during colitis and clarify its role in the maintenance of the intestinal epithelial barrier.

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