Abstract
Natural killer (NK) cells are important effector cells of the innate immune system to kill certain virus-infected and transformed cells. Wiskott–Aldrich Syndrome protein (WASP) and SCAR homolog (WASH) has been identified as a member of WASP family proteins implicated in regulating the cytoskeletal reorganization, yet little is known about its function in lymphocytes. Here we demonstrate that WASH is crucial for NK cell cytotoxicity. WASH was found to colocalize with lytic granules upon NK cell activation. Knockdown of WASH expression substantially inhibited polarization and release of lytic granules to the immune synapse, resulting in the impairment of NK cell cytotoxicity. More importantly, our data also define a previously unappreciated mechanism for WASH function, in which Src family kinase Lck can interact with WASH and induce WASH phosphorylation. Mutation of tyrosine residue Y141, identified here as the major site of WASH phosphorylation, partially blocked WASH tyrosine phosphorylation and NK cell cytotoxicity. Taken together, these observations suggest that WASH has a pivotal role for regulation of NK cell cytotoxicity through Lck-mediated Y141 tyrosine phosphorylation.
Highlights
Natural killer (NK) cells are the first defense line against viral infections and tumors.[1]
We have demonstrated that the recently identified Wiskott–Aldrich syndrome protein (WASP) family member WASP and SCAR homolog (WASH) has a significant role in control of NK cell cytotoxicity, indicating that this gene is not redundant with other WASP family members
We observed a defect in NK cell cytotoxicity in the absence of WASH expression
Summary
Natural killer (NK) cells are the first defense line against viral infections and tumors.[1]. Wiskott–Aldrich syndrome protein (WASP) is the first identified member of an actin regulator family.[5] WASP family proteins contain a C-terminal domain that binds to and activates the Arp2/3 complex for cytoskeleton remodeling.[6]. WASP and SCAR homolog (WASH) has been discovered as a new WASP family member.[9] Subsequent studies show that WASH interacts with multiple proteins, including FAM21, to form a large core complex and regulate actin dynamics.[10]. WASH complex activates Arp2/3-mediated actin polymerization and controls the production of transport intermediates from endosome.[11] Unlike other WASP family members, WASH has distinct N-terminal domains, termed WASH homology domain 1 (WHD1) and tubulin-binding region (TBR).[12]
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