Journal article
Nuclear role of WASp in gene transcription is uncoupled from its ARP2/3-dependent cytoplasmic role in actin polymerization
The Journal of immunology (1950), Vol.193(1), pp.150-160
07/01/2014
DOI: 10.4049/jimmunol.1302923
PMCID: PMC4137324
PMID: 24872192
Abstract
Defects in Wiskott-Aldrich Syndrome protein (WASp) underlie development of WAS, an X-linked immunodeficiency and autoimmunity disorder of childhood. Nucleation-promoting factors (NPFs) of the WASp family generate F-actin in the cytosol via the VCA (verprolin-homology, cofilin-homology, and acidic) domain and support RNA polymerase II-dependent transcription in the nucleus. Whether nuclear-WASp requires the integration of its actin-related protein (ARP)2/3-dependent cytoplasmic function to reprogram gene transcription, however, remains unresolved. Using the model of human TH cell differentiation, we find that WASp has a functional nuclear localizing and nuclear exit sequences, and accordingly, its effects on transcription are controlled mainly at the level of its nuclear entry and exit via the nuclear pore. Human WASp does not use its VCA-dependent, ARP2/3-driven, cytoplasmic effector mechanisms to support histone H3K4 methyltransferase activity in the nucleus of TH1-skewed cells. Accordingly, an isolated deficiency of nuclear-WASp is sufficient to impair the transcriptional reprogramming of TBX21 and IFNG promoters in TH1-skewed cells, whereas an isolated deficiency of cytosolic-WASp does not impair this process. In contrast, nuclear presence of WASp in TH2-skewed cells is small, and its loss does not impair transcriptional reprogramming of GATA3 and IL4 promoters. Our study unveils an ARP2/3:VCA-independent function of nuclear-WASp in TH1 gene activation that is uncoupled from its cytoplasmic role in actin polymerization.
Details
- Title: Subtitle
- Nuclear role of WASp in gene transcription is uncoupled from its ARP2/3-dependent cytoplasmic role in actin polymerization
- Creators
- Sanjoy Sadhukhan - Division of Pediatric Hematology-Oncology, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15213Koustav Sarkar - Division of Pediatric Hematology-Oncology, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15213; Division of Pediatric Hematology-Oncology, University of Iowa Children's Hospital, Iowa City, IA 52242; andMatthew Taylor - Division of Pediatric Hematology-Oncology, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15213Fabio Candotti - Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892Yatin M Vyas - Division of Pediatric Hematology-Oncology, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15213; Division of Pediatric Hematology-Oncology, University of Iowa Children's Hospital, Iowa City, IA 52242; and yatin-vyas@uiowa.edu
- Resource Type
- Journal article
- Publication Details
- The Journal of immunology (1950), Vol.193(1), pp.150-160
- DOI
- 10.4049/jimmunol.1302923
- PMID
- 24872192
- PMCID
- PMC4137324
- NLM abbreviation
- J Immunol
- ISSN
- 0022-1767
- eISSN
- 1550-6606
- Grant note
- R01 AI073561 / NIAID NIH HHS Intramural NIH HHS R01AI073561 / NIAID NIH HHS R01AI084957 / NIAID NIH HHS R01 AI084957 / NIAID NIH HHS R21 AI079762 / NIAID NIH HHS
- Language
- English
- Date published
- 07/01/2014
- Academic Unit
- Stead Family Department of Pediatrics
- Record Identifier
- 9984093216802771
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