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Constitutive activation of WASp in X-linked neutropenia renders neutrophils hyperactive.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2018 Aug 31; Vol. 128 (9), pp. 4115-4131. Date of Electronic Publication: 2018 Aug 20. - Publication Year :
- 2018
-
Abstract
- Congenital neutropenia is characterized by low absolute neutrophil numbers in blood, leading to recurrent bacterial infections, and patients often require life-long granulocyte CSF (G-CSF) support. X-linked neutropenia (XLN) is caused by gain-of-function mutations in the actin regulator Wiskott-Aldrich syndrome protein (WASp). To understand the pathophysiology in XLN and the role of WASp in neutrophils, we here examined XLN patients and 2 XLN mouse models. XLN patients had reduced myelopoiesis and extremely low blood neutrophil number. However, their neutrophils had a hyperactive phenotype and were present in normal numbers in XLN patient saliva. Murine XLN neutrophils were hyperactivated, with increased actin dynamics and migration into tissues. We provide molecular evidence that the hyperactivity of XLN neutrophils is caused by WASp in a constitutively open conformation due to contingent phosphorylation of the critical tyrosine-293 and plasma membrane localization. This renders WASp activity less dependent on regulation by PI3K. Our data show that the amplitude of WASp activity inside a cell could be enhanced by cell-surface receptor signaling even in the context in which WASp is already in an active conformation. Moreover, these data categorize XLN as an atypical congenital neutropenia in which constitutive activation of WASp in tissue neutrophils compensates for reduced myelopoiesis.
- Subjects :
- Animals
Congenital Bone Marrow Failure Syndromes
Female
Gain of Function Mutation
Gene Knock-In Techniques
Humans
Male
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Transgenic
Neutropenia congenital
Neutrophils ultrastructure
Phagocytosis
Phosphorylation
Protein Conformation
Wiskott-Aldrich Syndrome Protein chemistry
Genetic Diseases, X-Linked genetics
Genetic Diseases, X-Linked metabolism
Neutropenia genetics
Neutropenia metabolism
Neutrophils metabolism
Wiskott-Aldrich Syndrome Protein genetics
Wiskott-Aldrich Syndrome Protein metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 128
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 30124469
- Full Text :
- https://doi.org/10.1172/JCI64772