Formation of a WIP-, WASp-, actin-, and myosin IIA-containing multiprotein complex in activated NK cells and its alteration by KIR inhibitory signaling.
The tumor natural killer (NK) cell line YTS was used to examine the cytoskeletal rearrangements required for cytolysis. A multiprotein complex weighing approximately 1.3 mD and consisting of WASp-interacting protein (WIP), Wiskott-Aldrich syndrome protein (WASp), actin, and myosin IIA that formed during NK cell activation was identified. After induction of an inhibitory signal, the recruitment of actin and myosin IIA to a constitutive WIP-WASp complex was greatly decreased. Both actin and myosin IIA were recruited to WIP in the absence of WASp. This recruitment correlated with increased WIP phosphorylation, which was mediated by PKCtheta. Furthermore, the disruption of WIP expression by WIP RNA interference prevented the formation of this protein complex and led to almost complete inhibition of cytotoxic activity. Thus, the multiprotein complex is important for NK cell function, killer cell immunoglobulin-like receptor inhibitory signaling affects proteins involved in cytoskeletal rearrangements, and WIP plays a central role in the formation of the complex and in the regulation of NK cell activity.
Krzewski
Konrad
K
Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
Chen
Xi
X
Orange
Jordan S
JS
Strominger
Jack L
JL
D000199:Actins / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins; D003599:Cytoskeleton / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D025461:Feedback, Physiological / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000378:metabolism; D007694:Killer Cells, Natural / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000502:physiology; D046911:Macromolecular Substances / Q000378:metabolism; D018994:Myosin Light Chains / Q000378:metabolism; D024507:Nonmuscle Myosin Type IIA / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D000074121:Protein Kinase C-theta; D034622:RNA Interference; D011971:Receptors, Immunologic / Q000378:metabolism*; D054342:Receptors, KIR2DL1; D015398:Signal Transduction / Q000502:physiology; D051316:Wiskott-Aldrich Syndrome Protein / Q000378:metabolism*
D000199:Actins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; C093100:KIR2DL1 protein, human; D046911:Macromolecular Substances; D018994:Myosin Light Chains; D011971:Receptors, Immunologic; D054342:Receptors, KIR2DL1; C495767:WAS protein, human; C109903:WIPF1 protein, human; D051316:Wiskott-Aldrich Syndrome Protein; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D024507:Nonmuscle Myosin Type IIA