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Rictor/mTORC2 signaling protects colonocytes from apoptosis and prevents epithelial barrier breakdown.

Authors
  • Castro-Martinez, Felipe1
  • Candelario-Martinez, Aurora1
  • Encarnacion-Garcia, Maria Del Rocio1
  • Piedra-Quintero, Zayda2
  • Bonilla-Moreno, Raul2
  • Betanzos, Abigail3
  • Perez-Orozco, Rocio4
  • Hernandez-Cueto, Maria de Los Angeles5
  • Muñoz-Medina, Jose Esteban5
  • Patiño-Lopez, Genaro6
  • Schnoor, Michael2
  • Villegas-Sepulveda, Nicolas7
  • Nava, Porfirio8
  • 1 Departamento de Fisiología, Biofísica y Neurociencias del Centro de Investigación y de Estudios Avanzados (CINVESTAV), IPN. México DF, México.
  • 2 Departamento de Biomedicina Molecular del Centro de Investigación y de Estudios Avanzados (CINVESTAV), IPN. México DF, México.
  • 3 Departamento de Infectómica y Patogénesis Molecular del Centro de Investigación y de Estudios Avanzados (CINVESTAV), IPN. México DF, México.
  • 4 Programa MEDICI, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México. Ciudad de México, México.
  • 5 Laboratorio Central de Epidemiología, Instituto Mexicano del Seguro Social. Ciudad de México 02990. México.
  • 6 Laboratorio de Investigación en Inmunología y Proteómica, Hospital Infantil de México, Federico Gómez, Ciudad de México, México.
  • 7 Departamento de Biomedicina Molecular del Centro de Investigación y de Estudios Avanzados (CINVESTAV), IPN. México DF, México. Electronic address: [email protected]
  • 8 Departamento de Fisiología, Biofísica y Neurociencias del Centro de Investigación y de Estudios Avanzados (CINVESTAV), IPN. México DF, México. Electronic address: [email protected]
Type
Published Article
Journal
American Journal Of Pathology
Publisher
Elsevier
Publication Date
Jun 14, 2021
Identifiers
DOI: 10.1016/j.ajpath.2021.06.004
PMID: 34139193
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Epithelial barrier impairment is a hallmark of several pathological processes in the gut, including inflammatory bowel diseases. Several intracellular signals prevent apoptosis in intestinal epithelial cells. Here we shown that in colonocytes, rictor/mTORC2 signaling is a pro-survival stimulus. Mechanistically, mTORC2 activates Akt which in turns inhibits apoptosis by phosphorylating 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 clarifies its role in the maintenance of the intestinal epithelial barrier. Copyright © 2021. Published by Elsevier Inc.

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