Direct cleavage of ROCK II by granzyme B induces target cell membrane blebbing in a caspase-independent manner.
Caspase activation in target cells is a major function of granzyme B (grB) during cytotoxic lymphocyte granule-induced apoptosis. grB-mediated cell death can occur in the absence of active caspases, and the molecular targets responsible for this additional pathway remain poorly defined. Apoptotic plasma membrane blebbing is caspase independent during granule exocytosis-mediated cell death, whereas in other instances, this event is a consequence of the cleavage by caspases of the Rho effector, Rho-associated coiled coil-containing protein kinase (ROCK) I. We show here that grB directly cleaves ROCK II, a ROCK family member encoded by a separate gene and closely related to ROCK I, and this causes constitutive kinase activity and bleb formation. For the first time, two proteins of the same family are found to be specifically cleaved by either a caspase or grB, thus defining two independent pathways with similar phenotypic consequences in the cells. During granule-induced cell death, ROCK II cleavage by grB would overcome, for this apoptotic feature, the consequences of deficient caspase activation that may occur in virus-infected or malignant target cells.
Sebbagh
Michael
M
Institut National de la Santé et de la Recherche Medicale (INSERM) U461, IFR75, Faculté de Pharmacie, 92296 Châtenay-Malabry, France.
Hamelin
Jocelyne
J
Bertoglio
Jacques
J
Solary
Eric
E
Bréard
Jacqueline
J
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic; D004789:Enzyme Activation; D053804:Granzymes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D054460:rho-Associated Kinases
D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; C509213:GZMB protein, human; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases; D020169:Caspases