c-FLIPL regulates endoplasmic reticulum morphology and mitochondria-associated membranes functions

Elettra Sara Marini, Claudia Giampietri, Simonetta Petrungaro, Silvia Conti, Luca Scorrano, Elio Ziparo


Physical and functional interactions between endoplasmic reticulum (ER) and mitochondria take place at the mitochondria-associated membranes (MAMs), ER subdomains at the interface between the two organelles. Protein complexes at MAMs regulate lipid synthesis, Ca2+ signaling and apoptosis 1. Furthermore, they influence both ER and mitochondrial morphology, as their ablation is frequently associated to the dramatic remodeling of these organelles. Here we show that c-FLIPL (cellular FLICE-inhibitory protein, long isoform), mainly known as inhibitor of caspase-8, can be retrieved at the ER and MAMs. c-FLIP ablation in mouse embryonic fibroblasts (MEFs) impairs ER morphology and luminal contiguity, by inducing the proliferation of ER cisternae to the detriment of tubular ER. Furthermore, c-FLIPL controls the ER-mitochondria apposition, as the depletion of this protein physically uncouples the two organelles. Moreover, functionally, c-FLIP ablation lowers the cytosolic Ca2+-increase evoked either by agonists stimulation or by passive ER discharge and increases the resistance of c-FLIP-/- cells to ER stress-induced apoptosis. We also report that c-FLIP-/- cells show an increased caspase-mediated cleavage of the ER-shaping protein Reticulon-4 (which is a well-known regulator of ER biogenesis and morphology), at both basal level and upon TNFα-dependent apoptosis. In agreement with these findings, we finally show that c-FLIP absence enhances basal caspase-8 activation in c-FLIP-/- MEFs and that caspase-8 inhibition reverts morphological alterations in ER shape observed in c-FLIP-/- cells, suggesting a novel role for caspase-8 and c-FLIPL as regulators of ER functions and ER-mitochondria crosstalk.


endoplasmic reticulum; mitochondria-associated membranes; caspase-8; c-FLIP; Reticulon-4.

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DOI: http://dx.doi.org/10.13128/IJAE-14885

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