X-Linked thrombocytopenia causing mutations in WASP (L46P and A47D) impair T cell chemotaxis

Journal of Biomedical Science

Thirumaran Thanabalu¹  Bhawana George¹  Shijin Feng¹  Jun Hou Tan¹  Neeraj Jain¹ 

[1] School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore

关键词: Hematopoietic cell kinase;    Cell polarity;    Proteosome;    Actin cytoskeleton;    Cell migration;   

Others  :  1146331
DOI  :  10.1186/s12929-014-0091-1

 received in 2013-12-12, accepted in 2014-09-02,  发布年份 2014

【 摘 要 】

Background

Mutation in the Wiskott-Aldrich syndrome Protein (WASP) causes Wiskott-Aldrich syndrome (WAS), X-linked thrombocytopenia (XLT) and X-linked congenital neutropenia (XLN). The majority of missense mutations causing WAS and XLT are found in the WH1 (WASP Homology) domain of WASP, known to mediate interaction with WIP (WASP Interacting Protein) and CIB1 (Calcium and Integrin Binding).

Results

We analyzed two WASP missense mutants (L46P and A47D) causing XLT for their effects on T cell chemotaxis. Both mutants, WASP_R^L46P and WASP_R^A47D (S1-WASP shRNA resistant) expressed well in Jurkat^WASP-KD T cells (WASP knockdown), however expression of these two mutants did not rescue the chemotaxis defect of Jurkat^WASP-KD T cells towards SDF-1?. In addition Jurkat^WASP-KD T cells expressing these two WASP mutants were found to be defective in T cell polarization when stimulated with SDF-1?. WASP exists in a closed conformation in the presence of WIP, however both the mutants (WASP_R^L46P and WASP_R^A47D) were found to be in an open conformation as determined in the bi-molecular complementation assay. WASP protein undergoes proteolysis upon phosphorylation and this turnover of WASP is critical for T cell migration. Both the WASP mutants were found to be stable and have reduced tyrosine phosphorylation after stimulation with SDF-1?.

Conclusion

Thus our data suggest that missense mutations WASP_R^L46P or WASP_R^A47D affect the activity of WASP in T cell chemotaxis probably by affecting the turnover of the protein.

【 授权许可】

   
2014 Jain et al.; licensee BioMed Central Ltd.

【 图 表 】

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