The Jekyll and Hyde functions of caspases.

Apoptosis is an ancient form of regulated cell death that functions under pathological and nonpathological contexts in all metazoans. More than a decade of intense research has led to extensive characterization of the core molecular mechanisms for apoptotic cell death. This includes the identification of a family of cysteine proteases, caspases, which are critical for the execution of apoptosis. Whereas completion of the proteolytic caspase cascade leads to elimination of a cell by apoptosis, caspase activation, when finely tuned, directs alternative cellular functions independent of cell death. Exciting recent developments have focused on uncovering nonapoptotic roles of caspases ranging from immune regulation to spermatogenesis, in highly specialized cellular frameworks.

A genome-wide RNAi screen reveals multiple regulators of caspase activation.

Apoptosis is an evolutionally conserved cellular suicide mechanism that can be activated in response to a variety of stressful stimuli. Increasing evidence suggests that apoptotic regulation relies on specialized cell death signaling pathways and also integrates diverse signals from additional regulatory circuits, including those of cellular homeostasis. We present a genome-wide RNA interference screen to systematically identify regulators of apoptosis induced by DNA damage in Drosophila melanogaster cells. We identify 47 double- stranded RNA that target a functionally diverse set of genes, including several with a known function in promoting cell death. Further characterization uncovers 10 genes that influence caspase activation upon the removal of Drosophila inhibitor of apoptosis 1. This set includes the Drosophila initiator caspase Dronc and, surprisingly, several metabolic regulators, a candidate tumor suppressor, Charlatan, and an N-acetyltransferase, ARD1. Importantly, several of these genes show functional conservation in regulating apoptosis in mammalian cells. Our data suggest a previously unappreciated fundamental connection between various cellular processes and caspase-dependent cell death.

Innate recognition of bacteria by a macrophage cytosolic surveillance pathway.

Host recognition of bacterial pathogens is a critical component of the immune response. Intracellular bacterial pathogens are able to evade the humoral immune system by residing within the host cell. Here we show the existence of an innate host surveillance mechanism in macrophages that specifically distinguishes bacteria in the cytosol from bacteria in the vacuole. Recognition of Gram-positive and Gram-negative bacterial products by this surveillance system results in transcription of the ifnb gene. The activation of cytosol-specific signaling is associated with translocation of NF-kappaB into the nucleus and phosphorylation of the p38 mitogen-activated protein (MAP) kinase. Activation of the p38 kinase is required for the induction of gene expression by the cytosolic surveillance pathway. Our studies suggest that infection by intracellular bacterial pathogens results in an immune response distinct from that of infection by extracellular bacterial pathogens.