NLRX1 is a regulator of mitochondrial antiviral immunity.
The RIG-like helicase (RLH) family of intracellular receptors detect viral nucleic acid and signal through the mitochondrial antiviral signalling adaptor MAVS (also known as Cardif, VISA and IPS-1) during a viral infection. MAVS activation leads to the rapid production of antiviral cytokines, including type 1 interferons. Although MAVS is vital to antiviral immunity, its regulation from within the mitochondria remains unknown. Here we describe human NLRX1, a highly conserved nucleotide-binding domain (NBD)- and leucine-rich-repeat (LRR)-containing family member (known as NLR) that localizes to the mitochondrial outer membrane and interacts with MAVS. Expression of NLRX1 results in the potent inhibition of RLH- and MAVS-mediated interferon-beta promoter activity and in the disruption of virus-induced RLH-MAVS interactions. Depletion of NLRX1 with small interference RNA promotes virus-induced type I interferon production and decreases viral replication. This work identifies NLRX1 as a check against mitochondrial antiviral responses and represents an intersection of three ancient cellular processes: NLR signalling, intracellular virus detection and the use of mitochondria as a platform for anti-pathogen signalling. This represents a conceptual advance, in that NLRX1 is a modulator of pathogen-associated molecular pattern receptors rather than a receptor, and identifies a key therapeutic target for enhancing antiviral responses.
Moore
Chris B
CB
Department of Microbiology-Immunology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Bergstralh
Daniel T
DT
Duncan
Joseph A
JA
Lei
Yu
Y
Morrison
Thomas E
TE
Zimmermann
Albert G
AG
Accavitti-Loper
Mary A
MA
Madden
Victoria J
VJ
Sun
Lijun
L
Ye
Zhengmao
Z
Lich
John D
JD
Heise
Mark T
MT
Chen
Zhijian
Z
Ting
Jenny P-Y
JP
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular; D019295:Computational Biology; D006801:Humans; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000276:immunology* / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014779:Virus Replication; D014780:Viruses / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; C505371:MAVS protein, human; D024101:Mitochondrial Proteins; D016328:NF-kappa B; C527006:NLRX1 protein, human; D034741:RNA, Small Interfering; D016899:Interferon-beta