Fas-mediated apoptosis is regulated by the extracellular matrix protein CCN1 (CYR61) in vitro and in vivo.
Although Fas ligand (FasL) is primarily expressed by lymphoid cells, its receptor Fas (CD95/Apo-1) is broadly expressed in numerous nonlymphoid tissues and can mediate apoptosis of parenchymal cells upon injury and infiltration of inflammatory cells. Here we show that CCN1 (CYR61) and CCN2 (CTGF), matricellular proteins upregulated at sites of inflammation and wound repair, synergize with FasL to induce apoptosis by elevating cellular levels of reactive oxygen species (ROS). CCN1 acts through engagement of integrin alpha(6)beta(1) and cell surface heparan sulfate proteoglycans, leading to ROS-dependent hyperactivation of p38 mitogen-activated protein kinase in the presence of FasL to enhance mitochondrial cytochrome c release. We show that CCN1 activates neutral sphingomyelinase, which functions as a key source of CCN1-induced ROS critical for synergism with FasL. Furthermore, Fas-dependent hepatic apoptosis induced by an agonistic monoclonal anti-Fas antibody or intragastric administration of alcohol is severely blunted in knock-in mice expressing an apoptosis-defective Ccn1 allele. These results demonstrate that CCN1 is a physiologic regulator of Fas-mediated apoptosis and that the extracellular matrix microenvironment can modulate Fas-dependent apoptosis through CCN1 expression.
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago College of Medicine, Chicago, IL 60607, USA.
Vladislava
V
Juric
Chih-Chiun
CC
Chen
Lester F
LF
Lau
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D055515:Cysteine-Rich Protein 61 / Q000235:genetics / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D000431:Ethanol / Q000633:toxicity; D053222:Fas Ligand Protein / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D039121:Integrin alpha6beta1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism*
C501848:CCN1 protein, human; C491850:CCN1 protein, mouse; C526317:CCN2 protein, human; D002518:Ceramides; D055515:Cysteine-Rich Protein 61; D017931:DNA Primers; C491901:FAS protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C491899:Fas protein, mouse; C505658:Fasl protein, mouse; D019812:Heparan Sulfate Proteoglycans; D039121:Integrin alpha6beta1; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D019014:fas Receptor; D055513:Connective Tissue Growth Factor; D000431:Ethanol; D045304:Cytochromes c; D048308:Mitogen-Activated Protein Kinase 14; D013108:Sphingomyelin Phosphodiesterase; C519633:SMPD2 protein, human