FBXO22 inhibits colitis and colorectal carcinogenesis by regulating the degradation of the S2448-phosphorylated form of mTOR.

Abstract

Inflammatory bowel disease (IBD) is a considerable threat to human health with a significant risk for colorectal cancer (CRC). However, currently, both the molecular pathogenesis and therapeutic treatment of IBD remain limited. In this report, using both systemic and intestinal epithelium-specific gene knockout mouse models, we demonstrate that FBXO22, a substrate receptor within the SKP1-Cullin 1-F-box family of E3 ubiquitin ligases, plays an inhibitory role in the Azoxymethane/Dextran Sodium Sulfate-induced colorectal inflammatory responses and CRC. FBXO22 targets the serine 2448-phosphorylated form of mammalian mechanistic target of rapamycin (pS2448-mTOR) for ubiquitin-dependent degradation. This proteolytic targeting effect is established based on multiple lines of evidence including the results of colon tissue immunoblots, analysis of cultured cells with altered abundance of FBXO22 by depletion or overexpression, comparison of protein decay rate, effects on mTOR substrates S6K1 and 4E-BP1, analysis of protein-protein interactions, phosphor-peptide binding and competition, as well as reconstituted and cellular ubiquitination. Finally, we have shown that mTOR inhibitor rapamycin (RAPA) was able to alleviate the effects of fbxo22 deletion on colorectal inflammatory response and CRC. These RAPA effects are correlated with the ability of RAPA to inhibit pS2448-mTOR, pS6K1, and p4E-BP1. Collectively, our data support a suppressive role for FBXO22 in colorectal inflammation signaling and CRC initiation by targeting pS2448-mTOR for degradation.