Post-Translational Modifications of Transcription Factors Harnessing the Etiology and Pathophysiology in Colonic Diseases.

Chao-Yuan Hsu,Yu-Wen Liu,Shyi-Jou Chen,Shin-Huei Fu,Ming-Wei Chien,Huey-Kang Sytwu

doi:10.3390/ijms21093207

Abstract

Defects in mucosal immune balance can lead to colonic diseases such as inflammatory bowel diseases and colorectal cancer. With the advancement of understanding for the immunological and molecular basis of colonic disease, therapies targeting transcription factors have become a potential approach for the treatment of colonic disease. To date, the biomedical significance of unique post-translational modifications on transcription factors has been identified, including phosphorylation, methylation, acetylation, ubiquitination, SUMOylation, and O-GlcNAcylation. This review focuses on our current understanding and the emerging evidence of how post-translational regulations modify transcription factors involved in the etiology and pathophysiology of colonic disease as well as the implications of these findings for new therapeutic approaches in these disorders.

Highlights

Colonic diseases comprise a wide range of intestinal diseases, including inflammatory bowel disease (IBD), colon cancer, and diverticular disease
IBD, which includes ulcerative colitis (UC) and Crohn’s disease (CD), is regarded as a global problem because its prevalence is increasing in North America, Europe, and Asia, whereas its incidence is accelerating in newly industrialized countries [1,2]
Emergency surgery is needed for IBD patients when they are suffering from life-threatening complications, such as uncontrolled bleeding occurring from deep ulcerations, toxic megacolon, perforation of the colon, and the presence of fistula or abdominal abscess, that contribute to an increased mortality [12]

Summary

Introduction

Colonic diseases comprise a wide range of intestinal diseases, including inflammatory bowel disease (IBD), colon cancer, and diverticular disease. ILC and T helper cells are key in mediating the host protective and homeostatic responses, whereas they are known to be the main drivers of IBD In this part, we focus on the critical roles of PTMs in the positive or negative modulation of transcription factor-based cytokine regulation by targeting ILCs and CD4+ T cell differentiation towards inflammatory phenotypes and its implications for pathogenesis of the colonic diseases. C-Abl-mediated triple phosphorylation of T-bet at Tyr219/Tyr265/Tyr304 regulates its ability to bind to the DNA sequences of its target genes and modulates gene expression [44], and Tyr304-based phosphorylation of T-bet is required for formation of the T-bet–Runx complex that suppresses development of the Th17 cell lineage by inhibiting transcription of Rorc, which encodes the transcription factor of retinoic acid-related orphan receptor (RORγt) [45] These studies suggested that the transactivation ability of T-bet is regulated by phosphorylation and ubiquitination. FFiigguurree22..AAnnoovveerrvviieewwooff rreegguullaattiioonnffoorr ttrraannssccrriippttiioonnffaaccttoorrssSSTTAATT33,,IIRRFF44,,cc--MMaaffbbyyppoosstt--ttrraannssllaattioionnaall mmooddiifificcaattiioonnss iinn TT hheellppeerr cceelllsls. .TrTanrasncrsicprtiipotniofnacftaocrtsoSrsTASTTA3,TI3R, FI4R,Fc4-M, ca-fMaaref raergeurleagteudlabteydthbeyptohsetptorasnt-stlraatniosnlaatlionmalodmifoicdaitfiiocnatsion(Ps: (Pp:hpohsposhpohryolraytliaotnio; n;O:O:OO-G-GlclNcNAAcycylaltaitoino;n; SS:: SSUUMMOOyyllaattiioonn;; UU:: uubbiqiquuititininaatitoionn))aannddththeeccoololorrddiffifefererenncecessininddiciacatetevvaariroiouus smmooddifiifciactaitoionns soonnththeierirtatragrgetest.s

Blimp-1

Findings

Conclusions