INHIBITION OF ICE-LIKE PROTEASES INHIBITS APOPTOSIS AND INCREASES VIRUS PRODUCTION DURING ADENOVIRUS INFECTION

Interleukin-lb converting enzyme (ICE)-related cysteine proteases are required for E1A-induced, p53-dependent apoptosis in baby rat kidney ( BRK) cells. Adenovirus E1B 19K protein, which is a potent inhibitor of apoptosis, inhibits activation of these proteases in BRK cells. E1A e xpression induces apoptosis during infection of human cells by mutant adenoviruses which contain nonfunctional E1B 19K. The question arises as to whether ICE-related proteases are involved in E1A-induced apopto sis during mutant adenovirus infection of human cells. To test the inv olvement of the cysteine proteases in E1A-induced apoptosis during pro ductive adenovirus infection of HeLa cells, we examined whether Z-VAD- FMK, an inhibitor of ICE-related proteases, can inhibit apoptosis indu ced by mutant adenovirus which lacks functional E1B 19K. Z-VAD-FMK inh ibited E1A-induced apoptosis in adenovirus-infected Hela cells, sugges ting that the ICE family proteases are involved in this apoptosis path way. Z-VAD-FMK also inhibited cleavage of substrates such as cysteine protease CPP32 and nuclear lamins, whereas cleavage of poly(ADP-ribose ) polymerase was partially inhibited during infection with an E1B 19K mutant. Inhibition of apoptosis by Z-VAD-FMK significantly enhanced pr oduction of infectious adenovirus and attenuated virus release. Thus a poptosis may be a method for the host cell to limit virus production a nd release at the end of the infection cycle. (C) 1998 Academic Press.