Non-muscle myosin IIB helps mediate TNF cell death signaling independent of actomyosin contractility (AMC).
Non-muscle myosin II (NM II) helps mediate survival and apoptosis in response to TNF-alpha (TNF), however, NM II's mechanism of action in these processes is not fully understood. NM II isoforms are involved in a variety of cellular processes and differences in their enzyme kinetics, localization, and activation allow NM II isoforms to have distinct functions within the same cell. The present study focused on isoform specific functions of NM IIA and IIB in mediating TNF induced apoptosis. Results show that siRNA knockdown of NM IIB, but not NM IIA, impaired caspase cleavage and nuclear condensation in response to TNF. NM II's function in promoting cell death signaling appears to be independent of actomyosin contractility (AMC) since treatment of cells with blebbistatin or cytochalasin D failed to inhibit TNF induced caspase cleavage. Immunoprecipitation studies revealed associations of NM IIB with clathrin, FADD, and caspase 8 in response to TNF suggesting a role for NM IIB in TNFR1 endocytosis and the formation of the death inducing signaling complex (DISC). These findings suggest that NM IIB promotes TNF cell death signaling in a manner independent of its force generating property.
Flynn
Patrick G
PG
Department of Cell Biology and Anatomy Miller School of Medicine, University of Miami, Miami, Florida 33136, USA.
Helfman
David M
DM
D000205:Actomyosin / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053181:Caspase 8 / Q000378:metabolism; D002966:Clathrin / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D008856:Microscopy, Fluorescence; D024507:Nonmuscle Myosin Type IIA / Q000235:genetics / Q000378:metabolism; D024501:Nonmuscle Myosin Type IIB / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D034622:RNA Interference; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D002966:Clathrin; C505535:Fadd protein, rat; D053200:Fas-Associated Death Domain Protein; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D000205:Actomyosin; D053181:Caspase 8; D024507:Nonmuscle Myosin Type IIA; D024501:Nonmuscle Myosin Type IIB