Koustav Sarkar, Sanjoy Sadhukhan, Seong-Su Han, Yatin M Vyas

In Wiskott-Aldrich syndrome (WAS), immunodeficiency and autoimmunity often co-manifest, yet how WAS mutations misregulate chromatin-signaling in Thelper (TH) cells favoring development of auto-inflammation over protective-immunity is unclear. Previously we identified an essential promoter-specific, co-activator role of nuclear-WASp in TH1 gene transcription. Here we identify SUMOylation as a novel post-translational modification of WASp, impairment of which converts nuclear-WASp from a transcriptional co-activator to a co-repressor of NF-κB-response genes in human (TH)1-differentiating cells. V75M, one of many disease-causing mutations occurring in SUMO*motif ((72)ψψψψKDxxxxSY(83)) of WASp, compromises WASp-SUMOylation, associates with COMMD1 to attenuate NF-κB-signaling, and recruits histone deacetylases-6 (HDAC6) to p300-marked promoters of NF-κB-response genes that pattern immunity but not inflammation. Consequently, proteins mediating adaptive-immunity (IFNG, STAT1, TLR1) are deficient whereas those mediating auto-inflammation (GM-CSF, TNFAIP2, IL-1β) are paradoxically increased in TH1-cells expressing SUMOylation-deficient WASp. Moreover, SUMOylation-deficient WASp favors ectopic development of TH17-like phenotype (↑IL17A, IL21, IL22, IL23R, RORC, and CSF2) under TH1-skewing conditions, suggesting a role for WASp in modulating TH1/TH17 plasticity. Notably, pan-histone deacetylase inhibitors lift promoter-specific repression imposed by SUMOylation-deficient WASp and restore misregulated gene expression. Our findings uncovering a SUMOylation-based mechanism controlling WASp's dichotomous roles in transcription may have implications for personalized therapy for patients carrying mutations that perturb WASp-SUMOylation.