Apoptosis, a form of cellular suicide, involves the activation of CED-3-related cysteine proteases (caspases). The regulation of caspases by apoptotic signals and the precise mechanism by which they kill the cell remain unknown. In Drosophila, different death-inducing stimuli induce the expression of the apoptotic activator reaper. Cell killing by reaper and two genetically linked apoptotic activators, hid and grim, requires caspase activity. A Drosophila caspase, named Drosophila caspase-1 (DCP-1), was identified and found to be structurally and biochemically similar to Caenorhabditis elegans CED-3. Loss of zygotic DCP-1 function in Drosophila caused larval lethality and melanotic tumors, showing that this gene is essential for normal development.
Therapeutic monoclonal antibodies are the fastest growing class of biological therapeutics for the treatment of various cancers and inflammatory disorders. In cancer immunotherapy, some IgG1 antibodies rely on the Fc-mediated immune effector function, antibody-dependent cellular cytotoxicity (ADCC), as the major mode of action to deplete tumor cells. It is well-known that this effector function is modulated by the N-linked glycosylation in the Fc region of the antibody. In particular, absence of core fucose on the Fc N-glycan has been shown to increase IgG1 Fc binding affinity to the FcγRIIIa present on immune effector cells such as natural killer cells and lead to enhanced ADCC activity. As such, various strategies have focused on producing afucosylated antibodies to improve therapeutic efficacy. This review discusses the relevance of antibody core fucosylation to ADCC, different strategies to produce afucosylated antibodies, and an update of afucosylated antibody drugs currently undergoing clinical trials as well as those that have been approved.
We have identified a Drosophila homolog of Apaf-1 and ced-4, termed hac-1. Like mammalian APAF-1, HAC-1 can activate caspases in a dATP-dependent manner in vitro. During embryonic development, hac-1 is prominently expressed in regions where cells undergo natural death. Significantly, hac-1 transcription is also rapidly induced upon ionizing irradiation, similar to the proapoptotic gene reaper. Loss of hac-1 function causes reduced cell death, and reducing the dosage of hac-1 suppresses ectopic cell killing upon expression of the dcp-1 procaspase in the retina but has little effect on reaper, hid, and grim-mediated killing. Our data indicate that caspase activation and apoptosis in Drosophila are independently controlled by at least two distinct regulatory pathways that converge at the level of caspase activation.
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