Actin cytoskeletal defects in immunodeficiency

Abstract

The importance of the cytoskeleton in mounting a successful immune response is evident from the wide range of defects that occur in actin-related primary immunodeficiencies (PIDs). Studies of these PIDs have revealed a pivotal role for the actin cytoskeleton in almost all stages of immune system function, from hematopoiesis and immune cell development, through to recruitment, migration, intercellular and intracellular signaling, and activation of both innate and adaptive immune responses. The major focus of this review is the immune defects that result from mutations in the Wiskott-Aldrich syndrome gene (WAS), which have a broad impact on many different processes and give rise to clinically heterogeneous immunodeficiencies. We also discuss other related genetic defects and the possibility of identifying new genetic causes of cytoskeletal immunodeficiency.

Keywords: WASp neutropenia; actin cytoskeleton; immunodeficiency.

Figure 1

WASp domain structure, interacting proteins, and activation. Cytosolic WASp exists in an auto-inhibited conformation, with the VCA domain tethered to the GBD and basic domains. This inactive state is stabilized by WIP binding to the EVH1 domain. WASp is activated by a variety of signals, including GTP-Cdc42, PIP2, and Y291 phosphorylation by SH3 kinases recruited by the polyproline domain. Toca1 aids WASp activation by displacing WIP, binds GTP-Cdc42, and is required for PIP2 activation of WASp. Activation is restricted to the cell cortex where PIP2 and GTP-Cdc42 are present. Upon activation, the VCA domain is free to bind to and activate Arp2/3. Active Arp2/3 then attaches to an existing actin filament, where Arp2 and Arp3 form the template for a new actin filament branched at a 70° angle from the parent filament.