Journal article
SUMOylation-disrupting WAS mutation converts WASp from a transcriptional activator to a repressor of NF-κB response genes in T cells
Blood, Vol.126(14), pp.1670-1682
10/01/2015
DOI: 10.1182/blood-2015-05-646182
PMCID: PMC4591791
PMID: 26261240
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, 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.
Details
- Title: Subtitle
- SUMOylation-disrupting WAS mutation converts WASp from a transcriptional activator to a repressor of NF-κB response genes in T cells
- Creators
- Koustav Sarkar - Division of Pediatric Hematology-Oncology, University of Iowa Children's Hospital, Iowa City, IASanjoy Sadhukhan - Division of Pediatric Hematology-Oncology, University of Iowa Children's Hospital, Iowa City, IASeong-Su Han - Division of Pediatric Hematology-Oncology, University of Iowa Children's Hospital, Iowa City, IAYatin M Vyas - Division of Pediatric Hematology-Oncology, University of Iowa Children's Hospital, Iowa City, IA
- Resource Type
- Journal article
- Publication Details
- Blood, Vol.126(14), pp.1670-1682
- DOI
- 10.1182/blood-2015-05-646182
- PMID
- 26261240
- PMCID
- PMC4591791
- ISSN
- 0006-4971
- eISSN
- 1528-0020
- Grant note
- R01 AI073561 / NIAID NIH HHS P30 CA086862 / NCI NIH HHS R01 AI084957 / NIAID NIH HHS
- Language
- English
- Date published
- 10/01/2015
- Academic Unit
- Stead Family Department of Pediatrics
- Record Identifier
- 9984093369402771
Metrics
29 Record Views