CIDE, a novel family of cell death activators with homology to the 45kDa subunit of the DNA fragmentation factor

Abstract

DFF45 is a subunit of the DNA fragmentation factor (DFF) that is cleaved by caspase-3 during apoptosis. However, the mechanism by which DFF45 regulates apoptotic cell death remains poorly understood. Here we report the identification and characterization of two mammalian genes, CIDE-A and CIDE-B, encoding highly related proteins with homology to the N-terminal region of DFF45. CIDE-A and CIDE-B were found to activate apoptosis in mammalian cells, which was inhibited by DFF45 but not by caspase inhibitors. Expression of CIDE-A induced DNA fragmentation in 293T cells, which was inhibited by DFF45, further suggesting that DFF45 inhibits the apoptotic activities of CIDEs. In addition to mammalian CIDE-A and CIDE-B, we identified DREP-1, a Drosophila melanogaster homolog of DFF45 that could inhibit CIDE-Amediated apoptosis. Mutant analysis revealed that the C-terminal region of CIDE-A was necessary and sufficient for killing whereas the region with homology to DFF45 located in the N-terminus was required for DFF45 to inhibit CIDE-A-induced apoptosis. CD95/ Fas-mediated apoptosis was enhanced by CIDEs but inhibited by DFF45. These studies suggest that DFF45 is evolutionarily conserved and implicate CIDEs as DFF45-inhibitable effectors that promote cell death and DNA fragmentation.

Functional analysis of FSP27 protein regions for lipid droplet localization, caspase-dependent apoptosis, and dimerization with CIDEA

“…Curiously, the first described function of CIDEs was promotion of apoptosis. FSP27, CIDEA, and CIDEB exert robust apoptotic activity upon ectopic expression in mammalian cells (5,8,11,13,17). CIDE proteins have a region of amino acid sequence homology in their NH 2 -terminal halves, termed the CIDE N domain, that is also present in the major proapoptotic nuclease DFF40 and its inhibitory partner protein DFF45 (11).…”

“…CIDE proteins have a region of amino acid sequence homology in their NH 2 -terminal halves, termed the CIDE N domain, that is also present in the major proapoptotic nuclease DFF40 and its inhibitory partner protein DFF45 (11). A CIDE C domain, present in their COOH-terminal halves, is found only in FSP27, CIDEA, and CIDEB (11). Although the physiological role of CIDE-induced apoptosis remains undetermined, recent studies for FSP27, CIDEA, and CIDEB have greatly illuminated the role of endogenous CIDE proteins and indicate that they have crucial roles in lipid metabolism (14 -16, 24, 33, 42, 44).…”

“…In mice, CIDEA is found only in brown adipocytes (13,44), whereas in humans a high level of CIDEA is noted in white adipocytes (26). CIDEB transcript is markedly enriched in human and murine liver, with expression also reported for murine kidney and intestine (11,13,15).…”

Genome‐wide examination of myoblast cell cycle withdrawal during differentiation

“…The expression of several pro-apoptotic proteins was down-regulated at D1, including ASK1 (Ichijo et al, 1997), CIDE-B (Inohara et al, 1998), ES18 , Granzyme B (Darmon and Bleackley, 1998), NIP3 (Chen et al, 1997;Yasuda et al, 1998), and the P2X ATP receptor (Brake et al, 1994; Table 2). Paradoxically, expression of the antiapoptotic regulator, IAP-A (Goyal, 2001), decreased more than 50%, whereas expression of NIX (Chen et al, 1999), a pro-apoptotic Bcl-2 family member, increased approximately twofold in differentiating C2C12 cells (Table 2).…”

Differential regulation of CIDEA and CIDEC expression by insulin via Akt1/2- and JNK2-dependent pathways in human adipocytes

“…The cell death-inducing DNA fragmentation factor-␣ -like effector (CIDE) family, i.e., CIDEA, CIDEB, and CIDEC (CIDE-3 or fat-specifi c protein 27), was identifi ed initially as a group of factors that induces apoptosis in mammalian cells ( 32,33 ). Recent studies using mice defi cient in CIDE proteins suggested that this class of protein is closely related to energy balance and obesity (34)(35)(36)(37).…”