Abstract
BackgroundDeath receptors on the cell surface and the interacting cytosolic molecules, adaptors and initiator caspases, are essential as core components of the extrinsic apoptotic signaling pathway. While the apoptotic machinery governing the extrinsic signaling pathway is well characterized in mammals, it is not fully understood in fish.ResultsWe identified and characterized orthologs of mammalian Fas, FADD and caspase-8 that correspond to the death receptor, adaptor and initiator caspase, from the Medaka fish (Oryzias latipes). Medaka Fas, caspase-8 and FADD exhibited protein structures similar to that of their mammalian counterparts, containing a death domain (DD), a death effector domain (DED) or both. Functional analyses indicated that these molecules possess killing activity in mammalian cell lines upon overexpression or following activation by apoptotic stimuli, suggesting similar pro-apoptotic functions in the extrinsic pathway as those in mammals. Genomic sequence analysis revealed that the Medaka fas (tnfrsf6), fadd and caspase-8 (casp8) genes are organized in a similar genomic structure as the mammalian genes. Database search and phylogenetic analysis revealed that the fas gene, but not the fadd and casp8 genes, appear to be present only in vertebrates.ConclusionOur results indicate that the core components necessary for the extrinsic apoptotic pathway are evolutionarily conserved in function and structure across vertebrate species. Based on these results, we presume the mechanism of apoptosis induction via death receptors was evolutionarily established during the appearance of vertebrates.
Highlights
Death receptors on the cell surface and the interacting cytosolic molecules, adaptors and initiator caspases, are essential as core components of the extrinsic apoptotic signaling pathway
The activation of effector caspases is the converging point of two major signal pathways: the extrinsic pathway initiated by ligation of cell surface receptors called "death receptors", including Fas (APO-1/CD95) and receptors for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and the intrinsic pathway triggered by cytochrome c release from mitochondria into the cytosol
We identified an expressed sequence tag (EST) clone ([GenBank: AU176749]) similar to FAS, an EST clone ([GenBank: AU242372]) similar to FADD and two EST clones ([GenBank: BJ006125] and [GenBank: AV670945]) similar to CASP8 in the Medaka cDNA library
Summary
Death receptors on the cell surface and the interacting cytosolic molecules, adaptors and initiator caspases, are essential as core components of the extrinsic apoptotic signaling pathway. While the apoptotic machinery governing the extrinsic signaling pathway is well characterized in mammals, it is not fully understood in fish. Activation of a family of cysteine proteases known as caspases induces the proteolytic cleavage of many critical proteins, leading to cell suicide [6]. The activation of effector caspases is the converging point of two major signal pathways: the extrinsic pathway initiated by ligation of cell surface receptors called "death receptors", including Fas (APO-1/CD95) and receptors for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and the intrinsic pathway triggered by cytochrome c release from mitochondria into the cytosol
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