Affiliation:
1. W. M. Keck Autoimmune Disease Center, Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, California 92037, USA.
Abstract
Intracellular proteases appear to be important mediators of apoptosis. Substrates cleaved by proteases during apoptosis include nuclear autoantigens targeted in systemic autoimmune diseases. Using human autoantibodies as probes, we demonstrate here that T cell apoptosis mediated by CD95 (Fas/APO-1) is associated with substantial cleavage of a subset of nuclear autoantigens (7 of 33 examined). This subset included poly (ADP-ribose) polymerase, the 70-kD protein of the U1 small nuclear ribonucleoprotein particle, lamin B, the nuclear mitotic apparatus protein NuMA, DNA topoisomerases I and II, and the RNA polymerase I upstream binding factor UBF. Several of the cleaved autoantigens are involved in ensuring the integrity and proper conformation of DNA in the nucleus through interactions with the nuclear matrix, suggesting the possibility that their cleavage may contribute to the collapse of nuclear structure during apoptosis. The relative cleavage kinetics indicated that the autoantigens were targeted at various times after induction of apoptosis, suggesting either differential accessibility or activation of distinct proteases during the cell death process. These data reinforce the hypothesis that apoptosis is accompanied by selective cleavage of key substrates and not by a generalized degradation of intracellular material.
Publisher
Rockefeller University Press
Subject
Immunology,Immunology and Allergy
Cited by
247 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献