The p35 relative, p49, inhibits mammalian and Drosophila caspases including DRONC and protects against apoptosis

Abstract

This study characterized the ability of a new member of the p35 family, p49, to inhibit a number of mammalian and insect caspases. p49 blocked apoptosis triggered by treatment with Fas ligand (FasL), Tumor necrosis factor-related apoptosisinducing ligand (TRAIL) or ultraviolet (UV) radiation but provided negligible protection against apoptosis induced by the chemotherapeutic drug cisplatin. The caspase cleavage site in p49 was determined, and mutation of the P1 residue of this site abolished the ability of p49 to inhibit caspases, implying that p49 inhibits caspases through an analogous suicide ± substrate mechanism to p35. Unlike p35, p49 inhibited the upstream insect caspase DRONC.

Phosphorylation Drives an Apoptotic Protein to Activate Antiapoptotic Genes

“…However, viruses either encode certain proteins or modulate cellular proteins to evade transcription repression and apoptosis (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). PML nuclear bodies and their associated proteins such as PML, Sp100 (ND10-associated speckled, 100 kDa), Daxx, and ATRX (␣ thalassemia/mental retardation syndrome X-linked) as cellular defenses against viruses have been studied extensively (42)(43)(44)(45)(46)(47)(48)(49)(50).…”

“…In contrast, during early infection, viruses protect cells from dying for their own benefit. For this, they generally initiate cell survival pathways by recruiting their encoded proteins (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Because viruses control many cellular processes utilizing a limited number of viral proteins, the function of the viral protein may depend on its localization in the cell during various stages of viral infection.…”

Human Bcl-2 cannot directly inhibit the Caenorhabditis elegans Apaf-1 homologue CED-4, but can interact with EGL-1

“…Here, we capitalised on the previously noted ability of active caspases to kill the yeast Saccharomyces cerevisiae (Hawkins et al, 2001;Hawkins et al, 1999;Hawkins et al, 2000a;Hawkins et al, 2000b;Jabbour et al, 2002;Jabbour et al, 2004;Kang et al, 1999), to reconstitute the core nematode apoptotic pathway and to explore the ability of Bcl-2 to interact with it. Caspase toxicity in yeast depends both on the enzyme adopting an active conformation, as well as its substrate specificity.…”

Viral Subversion of Apoptotic Enzymes: Escape from Death Row

“…p35 is least effective against caspase-2 and caspase-9. The related p49 protein from Spodoptera littoralis Nucleopolyhedrovirus (SlNPV) (34) inhibits a wider range of caspases compared with p35, including caspase-2 and caspase-9 as well as Drosophila Nedd2-like caspase (DRONC), a caspase-9-like initiator caspase (56,142) (Table 1). However, unlike p35, p49 cannot suppress DrICE activity, suggesting host-specific roles for this class of inhibitors (70).…”