TY - JOUR
T1 - NLRC3, a member of the NLR family of proteins, is a negative regulator of innate immune signaling induced by the DNA sensor STING
AU - Zhang, Lu
AU - Mo, Jinyao
AU - Swanson, Karen V.
AU - Wen, Haitao
AU - Petrucelli, Alex
AU - Gregory, Sean M.
AU - Zhang, Zhigang
AU - Schneider, Monika
AU - Jiang, Yan
AU - Fitzgerald, Katherine A.
AU - Ouyang, Songying
AU - Liu, Zhi Jie
AU - Damania, Blossom
AU - Shu, Hong Bing
AU - Duncan, Joseph A.
AU - Ting, Jenny P.Y.
N1 - Funding Information:
Supported by NIH grants CA156330, P01DK094779, and R37-AI029564, (J.P.-Y.T.); AI088255 (J.A.D.); AI107810 (B.D.); and DE 018281 and U19 AI1099665 (B.D. and J.P.-Y.T.); Burroughs Wellcome Fund Career Award for Medical Scientists (J.A.D.); and MOST grants 2014CB910400 and 2013CB911103 and NSFC grants 31200559 and 31330019 (S.O. and Z.-J.L.). We thank T.W. Mak for sharing Traf6 +/+ , Traf6 +/− , and Traf6 −/− cells, A. Baldwin and L. Su for materials, E. Miao for Burkholderia thaildensis , and R. Chen for support and discussion.
PY - 2014/3/20
Y1 - 2014/3/20
N2 - Stimulator of interferon genes (STING, also named MITA, MYPS, or ERIS) is an intracellular DNA sensor that induces type I interferon through its interaction with TANK-binding kinase 1 (TBK1). Here we found that the nucleotide-binding, leucine-rich-repeat-containing protein, NLRC3, reduced STING-dependent innate immune activation in response to cytosolic DNA, cyclic di-GMP (c-di-GMP), and DNA viruses. NLRC3 associated with both STING and TBK1 and impeded STING-TBK1 interaction and downstream type I interferon production. By using purified recombinant proteins, we found NLRC3 to interact directly with STING. Furthermore, NLRC3 prevented proper trafficking of STING to perinuclear and punctated region, known to be important for its activation. In animals, herpes simplex virus 1 (HSV-1)-infected Nlrc3-/- mice exhibited enhanced innate immunity and reduced morbidity and viral load. This demonstrates the intersection of two key pathways of innate immune regulation, NLR and STING, to fine tune host response to intracellular DNA, DNA virus, and c-di-GMP.
AB - Stimulator of interferon genes (STING, also named MITA, MYPS, or ERIS) is an intracellular DNA sensor that induces type I interferon through its interaction with TANK-binding kinase 1 (TBK1). Here we found that the nucleotide-binding, leucine-rich-repeat-containing protein, NLRC3, reduced STING-dependent innate immune activation in response to cytosolic DNA, cyclic di-GMP (c-di-GMP), and DNA viruses. NLRC3 associated with both STING and TBK1 and impeded STING-TBK1 interaction and downstream type I interferon production. By using purified recombinant proteins, we found NLRC3 to interact directly with STING. Furthermore, NLRC3 prevented proper trafficking of STING to perinuclear and punctated region, known to be important for its activation. In animals, herpes simplex virus 1 (HSV-1)-infected Nlrc3-/- mice exhibited enhanced innate immunity and reduced morbidity and viral load. This demonstrates the intersection of two key pathways of innate immune regulation, NLR and STING, to fine tune host response to intracellular DNA, DNA virus, and c-di-GMP.
UR - http://www.scopus.com/inward/record.url?scp=84896344782&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2014.01.010
DO - 10.1016/j.immuni.2014.01.010
M3 - Article
C2 - 24560620
AN - SCOPUS:84896344782
SN - 1074-7613
VL - 40
SP - 329
EP - 341
JO - Immunity
JF - Immunity
IS - 3
ER -