| Summary: | Mitochondria and the endoplasmic reticulum (ER) are two organelles that critically contribute to apoptosis induction. It is established that they communicate and several factors for this have been identified. However, how cell death signals are transmitted from mitochondria to ER is unknown. During my PhD, I found that the mitochondrial fission protein Fis1 conveys an apoptosis signal from mitochondria to the ER by physically interacting with Bap31, which facilitates its cleavage into the pro-apoptotic p20Bap31 fragment. Exogenous apoptosis inducers likewise use this signalling route and induce the procession of Bap31. Initiator caspases are the apical apoptosis proteases that comprise protein-protein interaction domains in their N-terminal prodomains, which allow them to aggregate through adaptor proteins. Procaspase-8 is one of the most prominent initiator caspase; yet there are only two known procaspase-8-activating complexes identified to date: DISC and Hip1/Hippi complex. The cleavage of Bap31 is reported to be mediated by procaspase-8. I have found that procaspase-8 is recruited to the Fis1-Bap31 platform early during apoptosis. Apoptosis stimulation induces the dimerization of Bap31 and an in-depth dissection of this tripartite protein complex revealed that the association between procaspase-8 and the Fis1-Bap31 complex is dependent on the vDED domain present in Bap31. This signalling pathway emanating from Fis1 or caused by the application of exogenous apoptosis signals eventually results in calcium release from the ER leading to cytosolic calcium elevation. Additionally, production of the proapoptotic p20Bap31 fragment was found to be necessary for this event. The released calcium ions are subsequently taken up by mitochondria to induce mitochondrial dysfunction via the permeability transition pore thereby establishing a feedback loop from the ER that activates mitochondria for apoptosis execution. Hence, the Fis1-Bap31 complex, which we named ARCosome, bridges two critical organelles for apoptosis signalling and serves as a novel platform to activate the initiator procaspase-8.
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