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

Summary 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. Graphical Abstract Highlights • TG2 interacts with GRP75 in mitochondria-associated membranes (MAMs) • TG2 influences the number of ER-mitochondria contact sites • TG2 regulates the interaction between IP3R3 and GRP75 • TG2 controls ER-mitochondrial Ca²⁺ flux and protein expression in MAMs TG2 is an enzyme that plays a key role in mitochondria homeostasis. D'eletto et al. found that TG2 interacts with GRP75, a protein localized in mitochondria-associated membranes (MAMs). TG2 regulates the number of ER-mitochondria contact sites and Ca²⁺ flux, suggesting a key regulatory role in MAMs. [ABSTRACT FROM AUTHOR]