SUMOylation-disrupting WAS mutation converts WASp from a transcriptional activator to a repressor of NF-κB response genes in T cells

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

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

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, proteinsmediating adaptive immunity (IFNG, STAT1, TLR1) are deficient, whereas thosemediating auto-inflammation (GM-CSF, TNFAIP2, IL-1β) areparadoxically increased inTH1 cells expressing SUMOylation-deficient WASp.Moreover, SUMOylationdeficient WASp favors ectopic development of the TH17-like phenotype (↑IL17A, IL21, IL22, IL23R,RORC,andCSF2)underTH1-skewing conditions, suggesting a role for WA Spinmodulating TH1/TH17plasticity. 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. (Blood. 2015;126(14):1670-1682).

Original languageEnglish (US)
Pages (from-to)1670-1682
Number of pages13
JournalBlood
Volume126
Issue number14
DOIs
StatePublished - Oct 1 2015

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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