Transglutaminase Type 2 Regulates ER-Mitochondria Contact Sites by Interacting with GRP75
Manuela D’Eletto,
Federica Rossin,
Luca Occhigrossi,
Maria Grazia Farrace,
Danilo Faccenda,
Radha Desai,
Saverio Marchi,
Giulia Refolo,
Laura Falasca,
Manuela Antonioli,
Fabiola Ciccosanti,
Gian Maria Fimia,
Paolo Pinton,
Michelangelo Campanella,
Mauro Piacentini
Affiliations
Manuela D’Eletto
Department of Biology, University of Rome “Tor Vergata,” Rome 00133, Italy
Federica Rossin
Department of Biology, University of Rome “Tor Vergata,” Rome 00133, Italy
Luca Occhigrossi
Department of Biology, University of Rome “Tor Vergata,” Rome 00133, Italy
Maria Grazia Farrace
Department of Biology, University of Rome “Tor Vergata,” Rome 00133, Italy
Danilo Faccenda
Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK
Radha Desai
Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK
Saverio Marchi
Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara 44122, Italy
Giulia Refolo
National Institute for Infectious Diseases IRCCS “L. Spallanzani,” Rome 00149, Italy
Laura Falasca
National Institute for Infectious Diseases IRCCS “L. Spallanzani,” Rome 00149, Italy
Manuela Antonioli
National Institute for Infectious Diseases IRCCS “L. Spallanzani,” Rome 00149, Italy
Fabiola Ciccosanti
National Institute for Infectious Diseases IRCCS “L. Spallanzani,” Rome 00149, Italy
Gian Maria Fimia
National Institute for Infectious Diseases IRCCS “L. Spallanzani,” Rome 00149, Italy; Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Lecce 73100, Italy
Paolo Pinton
Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara 44122, Italy
Michelangelo Campanella
Department of Biology, University of Rome “Tor Vergata,” Rome 00133, Italy; Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK; UCL Consortium for Mitochondrial Research, Gower Street, London WC1E 6BT, UK
Mauro Piacentini
Department of Biology, University of Rome “Tor Vergata,” Rome 00133, Italy; National Institute for Infectious Diseases IRCCS “L. Spallanzani,” Rome 00149, Italy; Corresponding author
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. : 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. Keywords: mitochondrial Ca2+, MAMs, GRP75, TG2, ER-mitochondria contact sites
