SUMOylation-disrupting WAS mutation converts WASp from a transcriptional activator to a repressor of NF-κB response genes in T cells.
In Wiskott-Aldrich syndrome (WAS), immunodeficiency and autoimmunity often comanifest, 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, coactivator role of nuclear-WASp in TH1 gene transcription. Here we identify small ubiquitin-related modifier (SUMO)ylation as a novel posttranslational modification of WASp, impairment of which converts nuclear-WASp from a transcriptional coactivator to a corepressor of nuclear factor (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 the 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.
Division of Pediatric Hematology-Oncology, University of Iowa Children's Hospital, Iowa City, IA.
Koustav
K
Sarkar
Division of Pediatric Hematology-Oncology, University of Iowa Children's Hospital, Iowa City, IA.
Sanjoy
S
Sadhukhan
Division of Pediatric Hematology-Oncology, University of Iowa Children's Hospital, Iowa City, IA.
Seong-Su
SS
Han
Division of Pediatric Hematology-Oncology, University of Iowa Children's Hospital, Iowa City, IA.
Yatin M
YM
Vyas
D056704:Adaptive Immunity / Q000235:genetics / Q000276:immunology; D015153:Blotting, Western; D002460:Cell Line; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology*; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D058207:Sumoylation; D018417:Th1 Cells / Q000276:immunology*; D015533:Transcriptional Activation / Q000502:physiology*; D014162:Transfection; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics*
D016328:NF-kappa B; C495767:WAS protein, human; D051316:Wiskott-Aldrich Syndrome Protein