Transglutaminase Type 2 Regulates ER-Mitochondria Contact Sites by Interacting with GRP75

D'Eletto, M and Rossin, F and Occhigrossi, L and Farrace, M G and Faccenda, D and Desai, R and Marchi, S and Refolo, G and Falasca, L and Antonioli, M and Ciccosanti, F and Fimia, G M and Pinton, P and Campanella, M and Piacentini, M (2018) Transglutaminase Type 2 Regulates ER-Mitochondria Contact Sites by Interacting with GRP75. Cell Reports, 25 (12). pp. 3573-3581.

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Abstract

Transglutaminase type 2 (TG2) is a multifunctional enzyme that plays a key role in mitochondria homeostasis under stressful cellular conditions. TG2 interactome analysis reveals an enzyme interaction with GRP75 (glucose-regulated protein 75). GRP75 localizes in mitochondria-associated membranes (MAMs) and acts as a bridging molecule between the two organelles by assembling the IP3R-GRP75-VDAC complex, which is involved in the transport of Ca2+ from the endoplasmic reticulum (ER) to mitochondria. We demonstrate that the TG2 and GRP75 interaction occurs in MAMs. The absence of the TG2-GRP75 interaction leads to an increase of the interaction between IP3R-3 and GRP75; a decrease of the number of ER-mitochondria contact sites; an impairment of the ER-mitochondrial Ca2+ flux; and an altered profile of the MAM proteome. These findings indicate TG2 is a key regulatory element of the MAMs.