RORγt protein modifications and IL-17-mediated inflammation

RORγt is a member of the ROR family of transcription factors, and is selectively expressed in Th17 cells, γδT cells, and innate lymphoid cells in mice and humans. RORγt cooperates with STAT3, IRF4, and BATF to induce Il17a transcription in human and murine Th17 cells. RORγt protein turnover is regulated by the interplay between its ubiquitination and deubiquitination. The ubiquitin E3 ligase ITCH, UBR5, and TRAF5 facilitate RORγt ubiquitination in mouse Th17 cells, whereas USP4, USP17, and USP19 promote its deubiquitination in human Th17 cells. DUBA indirectly promotes RORγt degradation by deubiquitinating UBR5 in murine Th17 cells, which promotes degradation of RORγt. SUMOylation of RORγt at K187 facilitates the recruitment of histone deacetylase HDAC2 and inhibits Il17a expression in mouse Th17 cells and IBD patients. In contrast, SUMOylation at K31 facilitates the recruitment of histone acetyltransferase KAT2A and enhances RORγt transcription activity in murine Th17 cells. DNA-binding and the transcriptional activity of RORγt are regulated via p300-mediated acetylation in mouse Th17 cells. HDAC1 inhibits Il17a transcription by reversing the effect of p300, whereas Sirtuin-1 enhances Il17a transcription. RORγt, the master transcription factor for cytokine interleukin (IL)-17, is expressed explicitly in Th17 cells, γδT cells, and type 3 innate lymphoid cells in mice and humans. Since dysregulated IL-17 expression is strongly linked to several human inflammatory diseases, the RORγt–IL-17 axis has been the focus of intense research. Recently, several studies have shown that RORγt is modified by multiple post-translational mechanisms, including ubiquitination, acetylation, SUMOylation, and phosphorylation. This review discusses how post-translational modifications modulate RORγt function and its turnover to regulate IL-17-driven inflammation. Broad knowledge of these pathways is crucial for a clear understanding of the pathogenic role of RORγt+IL-17+ cells and for the development of putative therapeutic strategies to target IL-17-driven diseases such as multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease. RORγt, the master transcription factor for cytokine interleukin (IL)-17, is expressed explicitly in Th17 cells, γδT cells, and type 3 innate lymphoid cells in mice and humans. Since dysregulated IL-17 expression is strongly linked to several human inflammatory diseases, the RORγt–IL-17 axis has been the focus of intense research. Recently, several studies have shown that RORγt is modified by multiple post-translational mechanisms, including ubiquitination, acetylation, SUMOylation, and phosphorylation. This review discusses how post-translational modifications modulate RORγt function and its turnover to regulate IL-17-driven inflammation. Broad knowledge of these pathways is crucial for a clear understanding of the pathogenic role of RORγt+IL-17+ cells and for the development of putative therapeutic strategies to target IL-17-driven diseases such as multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease. mechanism by which introns are removed, and exons or portions of exons are assembled to construct different isoforms of mature mRNA from a single pre-mRNA. can influence gene expression and generate transcriptome diversity within the genome; in turn, it provides a framework for differential subcellular specificity and functions of proteins. basic-helix-loop-helix transcription factor encoded by the AHR gene; ligand-activated factor that integrates environmental, dietary, microbial, and metabolic cues to control complex transcriptional programs in a ligand-, cell-type-, and context-specific manner. mechanism of gene regulation in which chromatin undergoes rearrangement from a condensed state to an open state (transcriptionally active), allowing binding of transcription factors and gene regulatory elements. CRNDE-h is a 1-kb long noncoding RNA, transcribed from chromosome 16q12.2. It is a proto-oncogene secreted from the exosomes of colorectal cancer patients. regions on the genome that do not code for proteins and are evolutionary conserved; involved in gene regulation, including transcription factor binding sites, and cis-regulatory elements. most commonly used experimental model to study psoriasis in rodents. Topical application of 5% IMQ cream induces localized scaly skin lesions similar to human psoriasis. category of intestinal disorders characterized by chronic inflammation of the gastrointestinal tract. Ulcerative colitis (UC) and Crohn’s disease (CD) are two major forms of IBD. consists of a three-layer fold of 11–12 alpha helices and 2–3 β-strands to which ligands bind on orthosteric as well as allosteric sites and can inhibit or activate the function of a protein. hetero-bifunctional small molecules that contain two active domains connected by a linker – one domain binds to the target protein, and the other to the E3 ligase. The ternary complex of E3 ligase, PROTAC, and the target protein brings the ubiquitination machinery in close proximity and facilitates ubiquitination and degradation of the target protein. recombination activating gene1 (RAG1) is involved in antibody and T-cell receptor V(D)J recombination. Deletion of Rag1 (Rag1–/– mice) impairs T cell and B cell development and deletes mature T and B cells from the immune system.