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WASP–WIP complex in the molecular pathogenesis of Wiskott–Aldrich syndrome
Author(s) -
Sasahara Yoji
Publication year - 2016
Publication title -
pediatrics international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.49
H-Index - 63
eISSN - 1442-200X
pISSN - 1328-8067
DOI - 10.1111/ped.12819
Subject(s) - wiskott–aldrich syndrome protein , wiskott–aldrich syndrome , pathogenesis , primary immunodeficiency , t cell receptor , lipid raft , flow cytometry , immunology , microbiology and biotechnology , biology , t cell , medicine , gene , genetics , signal transduction , actin cytoskeleton , cytoskeleton , immune system , cell
Wiskott–Aldrich syndrome (WAS) is an X‐linked primary immunodeficiency disease characterized by recurrent infection, thrombocytopenia, and eczema. The gene responsible for X‐linked WAS encodes the Wiskott–Aldrich syndrome protein (WASP), which is expressed in hematopoietic cells and which regulates T‐cell activation and cytoskeletal reorganization in T‐cell receptor (TCR) signaling. Here, I review my recent research on WASP and the WASP‐interacting protein (WIP) complex in T cells. I and my colleagues first established a diagnostic screening method using flow cytometry and genetic analysis, and elucidated the molecular pathogenesis in WAS patients with unique clinical manifestations. We investigated the mechanisms by which WASP is recruited to lipid rafts following TCR stimulation and to immunological synapses between antigen‐presenting cells and T cells. Subsequently, we elucidated the molecular mechanisms by which WASP is degraded by calpain and ubiquitinated by Cbl‐family proteins, which terminate WASP activation. More importantly, we found that WIP plays a critical role in WASP stability in T cells. These results provide new insights into the molecular pathogenesis of X‐linked WAS and have facilitated the identification of WIP deficiency as an autosomal recessive form of WAS.