Abstract
Actin polymerization is a fundamental cellular process regulating immune cell functions and the immune response. The Wiskott-Aldrich syndrome protein (WASp) is an actin nucleation promoting factor, which is exclusively expressed in hematopoietic cells, where it plays a key regulatory role in cytoskeletal dynamics. WASp interacting protein (WIP) was first discovered as the binding partner of WASp, through the use of the yeast two hybrid system. WIP was later identified as a chaperone of WASp, necessary for its stability. Mutations occurring at the WASp homology 1 domain (WH1), which serves as the WIP binding site, were found to cause the Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT). WAS manifests as an immune deficiency characterized by eczema, thrombocytopenia, recurrent infections, and hematopoietic malignancies, demonstrating the importance of WIP for WASp complex formation and for a proper immune response. WIP deficiency was found to lead to different abnormalities in the activity of various lymphocytes, suggesting differential cell-dependent roles for WIP. Additionally, WIP deficiency causes cellular abnormalities not found in WASp-deficient cells, indicating that WIP fulfills roles beyond stabilizing WASp. Indeed, WIP was shown to interact with various binding partners, including the signaling proteins Nck, CrkL and cortactin. Recent studies have demonstrated that WIP also takes part in non immune cellular processes such as cancer invasion and metastasis, in addition to cell subversion by intracellular pathogens. Understanding of numerous functions of WIP can enhance our current understanding of activation and function of immune and other cell types.
Highlights
Rearrangement of the actin cytoskeleton is a key cellular event important for multiple cell functions, and is a highly regulated process [1]
Following NK cell conjugation and activation, Wiskott-Aldrich syndrome protein (WASp) is recruited to the natural killer immunological synapse (NKIS) and forms a 1,300 kDa multiprotein complex, which consists of WASp interacting protein (WIP), actin, and myosin IIA [77]
IcsA binds to N-WASp, and through it, to WIP, thereby promoting actin polymerization, allowing these bacteria to migrate within host cells
Summary
Rearrangement of the actin cytoskeleton is a key cellular event important for multiple cell functions, and is a highly regulated process [1]. Actin polymerization is dependent on the initial polymerization of three or more G-actin monomers, acting as a stable nucleus to which additional actin monomers may be assembled Formation of these actin nuclei is promoted by actin nucleation proteins. WIP was first discovered as the binding partner of WASp associated with actin polymerization [17], and was later demonstrated to function as a chaperone of WASp [18,19]. Immune responses, mainly those that are dependent on cellular functions that require actin polymerization, are impaired in WAS patients. We review the various mechanisms of WIP activity, the importance of WIP for the functioning of immune cells, its newly discovered roles beyond the immune system, its involvement in the development of metastasis, and its subversion by certain intracellular pathogens
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