Nuclear Role of WASp in the Pathogenesis of Dysregulated T _H 1 Immunity in Human Wiskott-Aldrich Syndrome

Abstract

The clinical symptomatology in the X-linked Wiskott-Aldrich syndrome (WAS), a combined immunodeficiency and autoimmune disease resulting from WAS protein (WASp) deficiency, reflects the underlying coexistence of an impaired T helper 1 (T H 1) immunity alongside intact T H 2 immunity. This suggests a role for WASp in patterning T H subtype immunity, yet the molecular basis for the T H 1-T H 2 imbalance in human WAS is unknown. We have discovered a nuclear role for WASp in the transcriptional regulation of the T H 1 regulator gene TBX21 at the chromatin level. In primary T H 1-differentiating cells, a fraction of WASp is found in the nucleus, where it is recruited to the proximal promoter locus of the TBX21 gene, but not to the core promoter of GATA3 (a T H 2 regulator gene) or RORc (a T H 17 regulator gene). Genome-wide mapping demonstrates association of WASp in vivo with the gene-regulatory network that orchestrates T H 1 cell fate choice in the human T H cell genome. Functionally, nuclear WASp associates with H3K4 trimethyltransferase [RBBP5 (retinoblastoma-binding protein 5)] and H3K9/H3K36 tridemethylase [JMJD2A (Jumonji domain-containing protein 2A)] proteins, and their enzymatic activity in vitro and in vivo is required for achieving transcription-permissive chromatin dynamics at the TBX21 proximal promoter in primary differentiating T H 1 cells. During T H 1 differentiation, the loss of WASp accompanies decreased enrichment of RBBP5 and, in a subset of WAS patients, also of filamentous actin at the TBX21 proximal promoter locus. Accordingly, human WASpdeficient T H cells, from natural mutation or RNA interference-mediated depletion, demonstrate repressed TBX21 promoter dynamics when driven under T H 1-differentiating conditions. These chromatin derangements accompany deficient T-BET messenger RNA and protein expression and impaired T H 1 function, defects that are ameliorated by reintroducing WASp. Our findings reveal a

Nuclear localized FAM21 participates in NF-κB-dependent gene regulation in pancreatic cancer cells

“…Nuclear N-WASP can regulate RNA-polymerase-II-dependent transcription through a direct interaction with the PSF-NonO (polypyrimidinetract-binding-protein-associated splicing factor-non-Pou-domain octamer-binding protein, also known as p54 nrb ) complex, and this process is associated with polymerization of actin (Wu et al, 2006). By contrast, nuclear WASP modulates the transcription of the T helper 1 (T H 1) regulator gene TBX21 by association with H3K4 trimethyltransferase and H3K9/H3K36 tridemethylase, which is independent of Arp2/3-dependent actin polymerization (Sadhukhan et al, 2014;Taylor et al, 2010). A recent report has demonstrated that nuclear WAVE1 is required for transcriptional reprogramming in oocytes and embryonic development (Miyamoto et al, 2013).…”

“…Furthermore, our data show that FAM21 can interact with the promoter regions of key NF-kB target genes and that loss of FAM21 results in decreased p65 chromatin loading. It is noteworthy that other actin NPFs such as JMY, WASP, neuronal WASP (N-WASP) and WAVE1 have previously been observed in the nucleus and involved in gene transcription Miyamoto et al, 2013;Sadhukhan et al, 2014;Taylor et al, 2010;Wu et al, 2006;Zuchero et al, 2009). Nuclear N-WASP can regulate RNA-polymerase-II-dependent transcription through a direct interaction with the PSF-NonO (polypyrimidinetract-binding-protein-associated splicing factor-non-Pou-domain octamer-binding protein, also known as p54 nrb ) complex, and this process is associated with polymerization of actin (Wu et al, 2006).…”

The Wiskott-Aldrich syndrome protein permits assembly of a focused immunological synapse enabling sustained T-cell receptor signaling

“…In apparent contrast with our findings, a role for WASP in the nucleus of T cells has been recently established, showing that it controls the transcriptional regulation of T-bet at the chromatin level. 17 We, therefore, need to consider that WASP may play parallel but non-redundant roles in distinct intracellular compartments, converging towards a fine-tuning of key signaling pathways and transcriptional programs. …”

“…16 However, the role of WASP at the IS has been further challenged by the discovery that this protein can also be present in the nucleus, where it participates in the regulation of cytokine gene transcription. 17 In this context, the real-time observation of WASP-deficient T cells contacting APC is still missing and would help to elucidate whether WASP links IS dynamics and architecture to downstream T-cell signaling and activation.…”

Cellular functions of WASP family proteins at a glance

“…In the absence of WASP, T-helper (T H 0) cells primarily developed into T H 2 cells, which are more prone to promoting autoimmunity. They showed that WASP accumulates in the nucleus of T H 0 cells that have been activated through their T-cell receptor and stimulated to polarize toward a T H 1 phenotype, which is driven by the expression of the transcription factor T-BET (encoded by the TBX21 gene) (Taylor et al, 2010). WASP was found to associate with the TBX21 promoter, where it recruited the pre-initiation complex, chromatin-remodeling factors and subunits of the SWI/SNF CRC Taylor et al, 2010).…”