Loss of PHLPP protects against colitis by inhibiting intestinal epithelial cell apoptosis

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1852

Article

Wen, Yang-An¹  Li, Xin¹  Goretsky, Tatiana²  Weiss, Heidi L.¹  Barrett, Terrence A.²  Gao, Tianyan^1,3 

[1] Univ Kentucky, Markey Canc Ctr, Lexington, KY 40536 USA

[2] Univ Kentucky, Div Digest Dis & Nutr, Dept Internal Med, Lexington, KY 40536 USA

[3] Univ Kentucky, Dept Mol & Cellular Biochem, Lexington, KY 40536 USA

关键词: PHLPP;    Knockout mouse;    Intestine epithelial cell apoptosis;    Akt;    Inflammatory bowel disease;   

DOI  :  10.1016/j.bbadis.2015.07.012

来源: Elsevier

【 摘 要 】

A common feature of inflammatory bowel disease (IBD) is the loss of intestinal epithelial barrier function due to excessive apoptosis of intestinal epithelial cells (IECs). However, the molecular mechanism underlying increased IEC apoptosis remains unclear. Here, we investigated the role of PHLPP, a novel family of protein phosphatases, in regulating inflammation-induced IEC apoptosis in mouse models of colitis. Both Phlpp1 and Phlpp2 genes were deleted in mice. Compared with wild-type mice, PHLPP double knockout (DKO) mice were protected from colitis induced by DSS as demonstrated by lower histopathological scores, and this reduced susceptibility to colitis was associated with decreased apoptosis and increased Akt activity in IECs in vivo. In addition, epithelial organoids derived from PHLPP DKO mice were more resistant to inflammation-induced apoptosis while inhibition of Akt activity abolished the protective effect of PHLPP-loss. Furthermore, we found that PHLPP expression was significantly reduced in IECs following the induction of colitis by DSS and in human IBD patient samples. This inflammation-induced downregulation of PHLPP was partially blocked by treating cells with a proteasome inhibitor. Taken together, our results indicated that proteasome-mediated degradation of PHLPP at the onset of inflammation plays an important role in protecting IEC injury by inhibiting apoptosis. (C) 2015 Elsevier B.V. All rights reserved.

【 授权许可】

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