Biochemistry

Edited by: Steve Bunk M.P. Boldin, T.M. Goncharov, Y.V. Goltsev, D. Wallach, "Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death," Cell, 85:803-15, 1996. (Cited in more than 250 publications as of January 1998) Comments by David Wallach, Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel Photo: Mike Goldberg DIRECT ROUTE: David Wallach of the Weizmann Institute wrote a paper that he says provided the first evidence that receptors can signal through direct activation of proteases to begin apoptosis. Cell death and signal transduction are two of the most intensive research fields in biochemistry worldwide. The work described in this paper resulted in findings significant to both those fields. In so doing, it built upon two already-established points of knowledge. The first point was one to which the laboratory of David Wallach, a professor in the department of biological chemistry at the Weizmann Institute of Science in Rehovot, Israel, had made a significant contribution. This prior work showed that two receptors-p55 for tumor necrosis factor (TNF) and Fas/APO-1, a widely occurring cell surface receptor belonging to the tumor necrosis factor/nerve growth factor (TNF/NGF) family-interact with adapter molecules in an intracellular region known as the death domain to spark a series of mechanisms that result in cell death. The second point of knowledge was that the process of apoptosis, or genetically programmed cell death, is initiated by activation of a cascade of proteases, called caspases, that cleave specific cellular proteins. "The evident question was, what is the molecular link between the intracellular death domains on one hand and the caspases on the other hand?" Wallach says. Several death domain-containing adapter proteins had been identified prior to the research described in this paper. In 1995, DNA screening by Wallach's team identified an adapter protein that binds specifically to Fas/APO-1. They dubbed it MORT1 (the acronym is also the Latin word for "death"), although work in the United States published shortly thereafter led to similar results and a name change, to Fas-associating protein with death domain (FADD), Wallach notes wryly. here, an adapter protein called TRADD that binds to the p55 receptor was identified. Subsequently, the two adapter proteins were found to be also capable of binding to each other. The next step for Wallach's group, involving the work reported in this paper, was to screen a library of complementary DNA (cDNA) of a human B cell for proteins that bind to MORT1. This yielded clones of MORT1, of TRADD, and of a novel protein that occurs in multiple isoforms. Wallach's team named the novel protein MACH (the acronym is also Hebrew for "deteriorating"), but, again, researchers in the U.S. renamed it shortly thereafter. A third name, now generally accepted, is caspase-8, indicating that this particular isoform of the novel protein belongs to the death-related proteolytic enzymes. Wallach's team looked upstream from the death domain, searching for a region where caspase-8 could bind to MORT1. They found the region, now known as the death effector domain. There, caspase-8 is recruited to MORT1, which carries the enzyme to the Fas/APO-1 receptor, resulting in activation of caspase-8. In turn, this activates other cellular proteins involved in the death process downstream. "I think the paper actually made an impact or a contribution in several fields," Wallach reflects. "For scientists working in signaling, it was the first demonstration that receptors can signal not only through protein kinases, cyclic nucleotides, ion fluxes, and lipid metabolites, but through direct activation of proteases. For those working in cell death, aside from clarifying the mode of activation of caspases by this particular receptor family, this research provided strong further general evidence of the critical role of caspases in cell death by apoptosis." In the long run, these discoveries are important to continuing efforts to understand receptor-induced cell death involved in the pathology of a variety of disorders, including autoimmune diseases, graft rejection, and various viral diseases.

Biochemistry

Interested in reading more?

Become a Member of