Involvement of MACH, a Novel MORT1/FADD-Interacting Protease, in Fas/APO-1- and TNF Receptor–Induced Cell Death

Abstract

Fas/APO-1 and p55 tumor necrosis factor (TNF) receptor (p55-R) activate cellular mechanisms that result in cell death. Upon activation of these receptors, Fas/APO-1 binds a protein called MORT1 (or FADD) and p55-R binds a protein called TRADD. MORT1 and TRADD can also bind to each other. We have cloned a novel protein, MACH, that binds to MORT1. This protein exists in multiple isoforms, some of which contain a region that has proteolytic activity and shows marked sequence homology to proteases of the ICE/CED-3 family. Cellular expression of the proteolytic MACH isoforms results in cell death. Expression of MACH isoforms that contain an incomplete ICE/CED-3 region provides effective protection against the cytotoxicity induced by Fas/APO-1 or p55-R triggering. These findings suggest that MACH is the most upstream enzymatic component in the Fas/APO-1- and p55-R-induced cell death signaling cascades.

Requirement of protein kinase (Krs/MST) activation for MT-21-induced apoptosis

“…Fas activation is known to activate the caspase cascade by interacting directly with a signaling complex on the cell membrane (Boldin et al, 1996;Muzio et al, 1996). Although Fas ligands may represent possible candidates for antitumor agents, most tumor cells express low levels of Fas.…”

MyD genes in negative growth control

“…To activate NF-kB, TRADD interacts with serine/threonine kinase RIP and TRAF2, that are linked to the NIK/IkK cascade, and trigger the phosphorylation and degradation of IkB (Hsu et al, 1996a,b). On the other hand, to induce cell death, TRADD interacts with FADD, which in turn triggers the apoptotic caspase cascade (Boldin et al, 1996;Grimm et al, 1996;Hsu et al, 1996a;Muzio et al, 1996). Since in IL-1 signaling, MyD88 is responsible for recruiting IRAK, which interacts with TRAF6, it is the functional equivalent of TRADD in NF-kB activation by IL-1.…”

JNK activation is not required for Fas-mediated apoptosis

“…Fas and TNFR1 share a region of homology in the cytoplasmic tail, the death domain, which is critical for signalling apoptosis (Itoh et al, 1991;Tartaglia et al, 1993). The death domain recruits FADD upon Fas activation (Kischkel et al, 1995), this then recruits and activates caspase 8 (Muzio et al, 1996;Boldin et al, 1996). Other caspases, including 1 and 3, are subsequently activated (Enari et al, 1996) and caspase activation is necessary for Fas-mediated apoptosis (Tewari and Dixit, 1995).…”