title: Toll-like receptor 9 protects non-immune cells from stress by modulating mitochondrial ATP synthesis through the inhibition of SERCA2.
abstract: Toll-like receptor 9 (TLR9) has a key role in the recognition of pathogen DNA in the context of infection and cellular DNA that is released from damaged cells. Pro-inflammatory TLR9 signalling pathways in immune cells have been well investigated, but we have recently discovered an alternative pathway in which TLR9 temporarily reduces energy substrates to induce cellular protection from stress in cardiomyocytes and neurons. However, the mechanism by which TLR9 stimulation reduces energy substrates remained unknown. Here, we identify the calcium-transporting ATPase, SERCA2 (also known as Atp2a2), as a key molecule for the alternative TLR9 signalling pathway. TLR9 stimulation reduces SERCA2 activity, modulating Ca(2+) handling between the SR/ER and mitochondria, which leads to a decrease in mitochondrial ATP levels and the activation of cellular protective machinery. These findings reveal how distinct innate responses can be elicited in immune and non-immune cells--including cardiomyocytes--using the same ligand-receptor system.
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Shintani
authors.forename: Hannes C A
authors.initials: HC
authors.lastname: Drexler
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Kioka
authors.forename: Cesare M N
authors.initials: CM
authors.lastname: Terracciano
authors.forename: Steven R
authors.initials: SR
authors.lastname: Coppen
authors.forename: Hiromi
authors.initials: H
authors.lastname: Imamura
authors.forename: Masaharu
authors.initials: M
authors.lastname: Akao
authors.forename: Junichi
authors.initials: J
authors.lastname: Nakai
authors.forename: Ann P
authors.initials: AP
authors.lastname: Wheeler
authors.forename: Shuichiro
authors.initials: S
authors.lastname: Higo
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakayama
authors.forename: Seiji
authors.initials: S
authors.lastname: Takashima
authors.forename: Kenta
authors.initials: K
authors.lastname: Yashiro
authors.forename: Ken
authors.initials: K
authors.lastname: Suzuki
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005347:Fibroblasts / Q000502:physiology*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000502:physiology*; D011485:Protein Binding; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*; D013312:Stress, Physiological; D051217:Toll-Like Receptor 9 / Q000502:physiology*
chemical_list: C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D000255:Adenosine Triphosphate; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse; D002118:Calcium