Regnase-1 controls colon epithelial regeneration via regulation of mTOR and purine metabolism

Abstract

SignificanceIdiopathic inflammatory bowel disease (IBD) is associated with the gut microbiota and immune system of the host; however, the precise pathogenesis of IBD is poorly defined. We show that specific deletion of the endoribonuclease Regnase-1 in intestinal epithelial cells relieves the symptoms of experimental colitis during acute inflammation. Regnase-1 deficiency potentiates mTOR signaling and purine metabolism in the colon epithelium. These data provide insight into the role of epithelial Regnase-1 in IBD.

Gut epithelial TSC1/mTOR controls RIPK3-dependent necroptosis in intestinal inflammation and cancer

“…On the contrary, the rapamycin pretreatment regimen used here (rapamycin treatment for 3 days before DSS challenge and 2 days after DSS challenge) failed to ameliorate colitis symptoms in WT mice (Supplemental Figure 4, A and B, and Figure 4, B and C). Notably, more extended rapamycin treatment started after the DSS challenge has been associated with either reduced or enhanced colitis in WT mice (55,56). Hence, it seems possible to ameliorate IEC death and colitis by tempering mTOR activity.…”

Post‐transcriptional control of immune responses and its potential application

“…Regnase‐1 is also expressed in intestinal epithelial cells where it plays diverse roles. Regnase‐1 in colon epithelium is reported to regulate epithelial regeneration . The lack of Regnase‐1 specifically in intestinal epithelial cells shows resistance to the colitis induced by dextran sulphate sodium (DSS) presumably via the regulation of mTOR signalling and purine metabolism.…”

“…Regnase-1 in colon epithelium is reported to regulate epithelial regeneration. 59 The lack of Regnase-1 specifically in intestinal epithelial cells shows resistance to the colitis induced by dextran sulphate sodium (DSS) presumably via the regulation of mTOR signalling and purine metabolism. In addition to the immune regulation, Regnase-1 has a distinct function in the duodenum, the uppermost part in the intestine which absorbs most of the iron required for the body.…”

Somatic evolution in non-neoplastic IBD-affected colon

“…To our knowledge, mutations in the other two genes, PIGR and ZC3H12A, have not been described in cancer. ZC3H12A encodes an RNAse, Regnase-1, which potentiates the mechanistic target of rapamycin kinase (mTOR) and purine metabolism in epithelial cells 26 . Mice with intestinal epithelial cell-specific knock-out mutations of Zc3h12a are more resistant to dextran sulfate sodium-induced epithelial injury 26 -a common murine model of IBD.…”

“…ZC3H12A encodes an RNAse, Regnase-1, which potentiates the mechanistic target of rapamycin kinase (mTOR) and purine metabolism in epithelial cells 26 . Mice with intestinal epithelial cell-specific knock-out mutations of Zc3h12a are more resistant to dextran sulfate sodium-induced epithelial injury 26 -a common murine model of IBD. We hypothesize that mutations in ZC3H12A protect human colonic epithelial cells from the damaging effects of inflammation and facilitate rapid healing of the mucosa without predisposing to cancer.…”