Drug Discov Ther. 2008;2(1):14-23.

Sensing and reacting to dangers by caspases: Caspase activation via inflammasomes.

Takeishi A, Kuranaga E, Miura M


Caspases are well known as mediators of programmed cell death, or apoptosis, in which their functions are highly conserved throughout evolution. In addition to inducing apoptosis, caspases have important roles in immune reactions. As part of a cell's response to pathogens or alarm (cellular danger) signals from damaged cells, caspase-1 is activated by forming an inflammatory complex with apoptosisassociated speck like protein containing a caspase recruitment domain (ASC) and nucleotide-binding oligomerization domain like receptor (NLR) family proteins. The activated caspase-1 then cleaves and promotes the maturation of cytokines, such as IL-1β, IL-18, and IL-33. Although it has long been unclear how hosts recognize diverse stresses, including injury and pathogen infection, and react appropriately, recent analyses have revealed many details about the sensing mechanisms provided by NLRs. Members of the NLR family are activated and yield different outcomes depending on the stimulus. For example, the NLR member cryopyrin/NALP3 induces cytokine secretion and lipid synthesis in response to viral dsRNA and K+ efflux, while another NLR, IPAF, induces IL-1β? in response to the virulence protein, flagellin. Cryopyrin/NALP3-mediated caspase-1 activation is involved not only in the immune response to pathogens but also in the stress response to UV irradiation in human skin. In this review, we focus on the stress responses that particularly involve inflammatory caspases. Since host reactions to stresses have been studied in invertebrates as well as in mammals, we also review the caspase-mediated immune responses that have been identified in the fruit fly Drosophila melanogaster, and suggest that the contribution of caspases to general stress responses is evolutionally conserved.

KEYWORDS: Caspase, Inflammasome, Stress response, Danger signal, Drosophila

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