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Toll‐like receptor 9 protects non‐immune cells from stress by modulating mitochondrial ATP synthesis through the inhibition of SERCA 2
Author(s) -
Shintani Yasunori,
Drexler Hannes CA,
Kioka Hidetaka,
Terracciano Cesare MN,
Coppen Steven R,
Imamura Hiromi,
Akao Masaharu,
Nakai Junichi,
Wheeler Ann P,
Higo Shuichiro,
Nakayama Hiroyuki,
Takashima Seiji,
Yashiro Kenta,
Suzuki Ken
Publication year - 2014
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1002/embr.201337945
Subject(s) - tlr9 , microbiology and biotechnology , context (archaeology) , innate immune system , receptor , biology , immune system , mitochondrion , toll like receptor 9 , serca , pattern recognition receptor , signal transduction , calcium signaling , toll like receptor , stimulation , chemistry , atpase , biochemistry , immunology , neuroscience , gene expression , paleontology , gene , dna methylation , enzyme
Toll‐like receptor 9 ( TLR 9) 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 TLR 9 signalling pathways in immune cells have been well investigated, but we have recently discovered an alternative pathway in which TLR 9 temporarily reduces energy substrates to induce cellular protection from stress in cardiomyocytes and neurons. However, the mechanism by which TLR 9 stimulation reduces energy substrates remained unknown. Here, we identify the calcium‐transporting ATP ase, SERCA 2 (also known as Atp2a2), as a key molecule for the alternative TLR 9 signalling pathway. TLR 9 stimulation reduces SERCA 2 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.