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

作者：Jain Neeraj; Tan Jun Hou; Feng Shijin; George Bhawana; Thanabalu Thirumaran^*

来源：Journal of Biomedical Science, 2014, 21(1): 91.

DOI：10.1186/s12929-014-0091-1

• Cell migration
• Actin cytoskeleton
• Proteosome
• Cell polarity
• Hematopoietic cell kinase

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). %26lt;br%26gt;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 alpha. In addition JurkatWASP-KD T cells expressing these two WASP mutants were found to be defective in T cell polarization when stimulated with SDF-1 alpha. 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-1a. %26lt;br%26gt;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.

• 出版日期2014-9-9
• 单位南阳理工学院