Research ArticleWiskott-Aldrich Syndrome

Nuclear Role of WASp in the Pathogenesis of Dysregulated TH1 Immunity in Human Wiskott-Aldrich Syndrome

Science Translational Medicine  23 Jun 2010:
Vol. 2, Issue 37, pp. 37ra44
DOI: 10.1126/scitranslmed.3000813

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Nuclear Face of WASp

For nearly 15 years, the protein gone awry in the hereditary disease affecting young boys known as Wiskott-Aldrich syndrome, WASp, has been linked to its role in maintaining the cellular architecture by reorganizing actin filaments in response to specific signals. Patients affected by the disease develop immunological deficiencies, ranging from eczema and frequent infections, to fatal malignancies such as lymphomas and leukemias, ending the lives of these patients usually by the unripe age of 30. At the cellular and molecular level, the blood obtained from these WAS patients exhibited abnormal actin bundling properties within T lymphocytes, and it was postulated that the ability of WASp to reorganize actin is dependent upon the activation and binding of Cdc42 in response to extra-cellular stimuli. However, while speculations based on biochemical and structural motif analyses have hinted at alternative roles for WASp within the cell, the exact mechanism by which this is or is not the case has not been reported. Now, Yatin Vyas and colleagues take a closer look at the cells from WAS patients and uncover the nuclear face of WASp. In this study, nuclear WASp is directly involved at the transcriptional level by ensuring the precise acquisition of chromatin marks required for the differentiation of T helper 1 (TH1) cells or type 1 immunity, but not of TH2 cells, explaining the tipped balance between these two cell populations central to the immune deficiencies in WAS patients. Epigenetic regulation of T cell differentiation linked to cancerous malignancies offers an appealing avenue for targeted therapeutic intervention of this multifaceted protein.

Footnotes

  • * These authors contributed equally to this work.

  • Citation: M. D. Taylor, S. Sadhukhan, P. Kottangada, A. Ramgopal, K. Sarkar, S. D'Silva, A. Selvakumar, F. Candotti, Y. M. Vyas, Nuclear role of WASp in the pathogenesis of dysregulated TH1 immunity in human Wiskott-Aldrich syndrome. Sci. Transl. Med. 2, 37ra44 (2010).