Sumoylation of RORγt regulates TH17 differentiation and thymocyte development

Abstract

RORγt controls the differentiation of TH17 cells, which are mediators of autoimmune conditions such as experimental autoimmune encephalomyelitis (EAE). RORγt also regulates thymocyte development and lymph node genesis. Here we show that the function of RORγt is regulated by its sumoylation. Loss of Sumo3, but not Sumo1, dampens TH17 differentiation and delays the progression of thymic CD8+ immature single-positive cells (ISPs). RORγt is SUMO3-modified by E3 ligase PIAS4 at lysine 31 (K31), and the mutation of K31 to arginine in mice prevents RORγt sumoylation, leading to impaired TH17 differentiation, resistance to TH17-mediated EAE, accumulation of thymic ISPs, and a lack of Peyer’s patches. Mechanistically, sumoylation of RORγt-K31 recruits histone acetyltransferase KAT2A, which stabilizes the binding of SRC1 to enhance RORγt transcription factor activity. This study thus demonstrates that sumoylation is a critical mechanism for regulating RORγt function, and reveals new drug targets for preventing TH17-mediated autoimmunity.

SUMO and Transcriptional Regulation: The Lessons of Large-Scale Proteomic, Modifomic and Genomic Studies

“…Though less frequent, recruitment of coactivators by SUMOylated TFs to promote transcription has also been reported ( Figure 4 ). This is, for example the cases of (i) the TF Bcl11b whose SUMOylated form can recruit the HAT p300 to derepress genes it otherwise represses during T-cell development [ 113 ], (ii) the CLOCK1/BMAL1 transcriptional complex, which, upon SUMOylation of its BMAL1 moiety during the resetting of the circadian clock, recruits the HATs CBP/p300 [ 153 ], and (iii) the TF RORγT, which recruits the HAT KAT2A by during the differentiation of T H 17 cells [ 243 ]. Alternatively, coactivators can be recruited in a SUMO-dependent manner by other coregulators to promote the transcription of certain genes.…”

Role of Epigenetics in the Regulation of Immune Functions of the Skin

“…DNA demethylation promotes Th17 development by TET2 (Ichiyama et al, 2015) but negatively regulates these functions by TET2/3 (Nakatsukasa et al, 2019). DNA demethylation, histone deacetylation, and SUMOylation show different effects depending on targeted epigenetic enzymes (Gardner et al, 2013;He et al, 2018;Ichiyama et al, 2015;Lim et al, 2015;Nakatsukasa et al, 2019;Singh et al, 2018;Yan et al, 2017). Histone methylation negatively regulates IL-17 production (Antignano et al, 2014), whereas histone demethylation also showed both positive and negative regulation of Th17 development (Cribbs et al, 2020;Itoh et al, 2019;Li et al, 2014;Liu et al, 2018aLiu et al, , 2015.…”

RORγ Structural Plasticity and Druggability

“…Several questions need to be answered before attempting this for RORγ. It is known that mutations at Ser 38 , Lys 52 and Lys 90 decrease the binding of the RORγ DBD to the HRE [ 47 , 48 , 49 ]. The residues are situated in the zinc finger motif, SUMOylation site and ubiquitination site of the DBD, respectively, which are potential candidate sites for drug targeting.…”