The endoplasmic reticulum-resident protein TMCC-1 localizes NLRC3 to the ER to control type I interferon production 2816

Abstract Description Recognition of cytosolic nucleic acids is a critical step in the production of type I interferons. One apical sensor, cGAS, binds to cytosolic DNA in a sequence independent manner. DNA-bound cGAS generates a 2’3’ cyclic GMP-AMP (cGAMP) nucleotides as secondary messengers that bind directly STING at the endoplasmic reticulum. Active STING oligomerizes and recruits TBK-1 or IKKε, which phosphorylates interferon regulatory factors to drive the antiviral transcriptome. NLRC3 is a member of the nucleotide-binding domain, leucine-rich repeat containing protein (NLR) family that negatively regulates this pathway by inhibiting STING trafficking and TBK-1 activity, thus decreasing the amount of secreted type I interferon. TMCC1 was identified as a putative interacting partner of NLRC3 via a yeast-two hybrid screen. In this article we demonstrate that TMCC1 interacts with NLRC3, at or near the ER. This interaction prevents efficient NLRC3 interactions with STING. TMCC1 also interacts with cGAS and IKKε but not additional proteins associated with cytosolic DNA sensing. In addition, recombinant THP-1 cells deficient in TMCC1 secrete significantly less type I interferon in response to different cytosolic DNA molecules. These findings suggest that TMCC1 is a positive regulator of type I interferon production in response to cytosolic DNA, possibly via derepressing NLRC3 function and/or via interactions with cGAS and IKKε. Funding Sources Supported by NIH R15GM134430 Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)