X-Linked thrombocytopenia causing mutations in WASP (L46P and A47D) impair T cell chemotaxis
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 m...
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sg-ntu-dr.10356-1019332023-02-28T17:05:33Z X-Linked thrombocytopenia causing mutations in WASP (L46P and A47D) impair T cell chemotaxis Jain, Neeraj Tan, Jun Hou Feng, Shijin George, Bhawana Thanabalu, Thirumaran School of Biological Sciences DRNTU::Science::Biological sciences 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, WASPRL46P and WASPRA47D (S1-WASP shRNA resistant) expressed well in JurkatWASP-KD T cells (WASP knockdown), however expression of these two mutants did not rescue the chemotaxis defect of JurkatWASP-KD T cells towards SDF-1α. In addition JurkatWASP-KD T cells expressing these two WASP mutants were found to be defective in T cell polarization when stimulated with SDF-1α. WASP exists in a closed conformation in the presence of WIP, however both the mutants (WASPRL46P and WASPRA47D) 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-1α. Conclusion: Thus our data suggest that missense mutations WASPRL46P or WASPRA47D affect the activity of WASP in T cell chemotaxis probably by affecting the turnover of the protein. Published version 2014-11-10T09:04:00Z 2019-12-06T20:46:53Z 2014-11-10T09:04:00Z 2019-12-06T20:46:53Z 2014 2014 Journal Article Jain, N., Tan, J. H., Feng, S., George, B., & Thanabalu, T. (2014). X-Linked thrombocytopenia causing mutations in WASP (L46P and A47D) impair T cell chemotaxis. Journal of biomedical science, 21(1), 91-. 1423-0127 https://hdl.handle.net/10356/101933 http://hdl.handle.net/10220/24212 10.1186/s12929-014-0091-1 25200405 en Journal of biomedical science © 2014 Jain et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. 12 p. application/pdf |
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DRNTU::Science::Biological sciences Jain, Neeraj Tan, Jun Hou Feng, Shijin George, Bhawana Thanabalu, Thirumaran X-Linked thrombocytopenia causing mutations in WASP (L46P and A47D) impair T cell chemotaxis |
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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, WASPRL46P and WASPRA47D (S1-WASP shRNA resistant) expressed well in JurkatWASP-KD T cells (WASP knockdown), however expression of these two mutants did not rescue the chemotaxis defect of JurkatWASP-KD T cells towards SDF-1α. In addition JurkatWASP-KD T cells expressing these two WASP mutants were found to be defective in T cell polarization when stimulated with SDF-1α. WASP exists in a closed conformation in the presence of WIP, however both the mutants (WASPRL46P and WASPRA47D) 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-1α. Conclusion: Thus our data suggest that missense mutations WASPRL46P or WASPRA47D affect the activity of WASP in T cell chemotaxis probably by affecting the turnover of the protein. |
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School of Biological Sciences |
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School of Biological Sciences Jain, Neeraj Tan, Jun Hou Feng, Shijin George, Bhawana Thanabalu, Thirumaran |
format |
Article |
author |
Jain, Neeraj Tan, Jun Hou Feng, Shijin George, Bhawana Thanabalu, Thirumaran |
author_sort |
Jain, Neeraj |
title |
X-Linked thrombocytopenia causing mutations in WASP (L46P and A47D) impair T cell chemotaxis |
title_short |
X-Linked thrombocytopenia causing mutations in WASP (L46P and A47D) impair T cell chemotaxis |
title_full |
X-Linked thrombocytopenia causing mutations in WASP (L46P and A47D) impair T cell chemotaxis |
title_fullStr |
X-Linked thrombocytopenia causing mutations in WASP (L46P and A47D) impair T cell chemotaxis |
title_full_unstemmed |
X-Linked thrombocytopenia causing mutations in WASP (L46P and A47D) impair T cell chemotaxis |
title_sort |
x-linked thrombocytopenia causing mutations in wasp (l46p and a47d) impair t cell chemotaxis |
publishDate |
2014 |
url |
https://hdl.handle.net/10356/101933 http://hdl.handle.net/10220/24212 |
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1759853132747112448 |