Viral DNA Binding to NLRC3, an Inhibitory Nucleic Acid Sensor, Unleashes STING, a Cyclic Dinucleotide Receptor that Activates Type I Interferon

Xin Li; Meng Deng; Alex S Petrucelli; Cheng Zhu; Jinyao Mo; Lu Zhang; Jason W Tam; Pablo Ariel; Baoyu Zhao; Song Zhang; Hengming Ke; Pingwei Li; Nikolay V Dokholyan; Joseph A Duncan; Jenny P-Y Ting

doi:10.1016/j.immuni.2019.02.009

Viral DNA Binding to NLRC3, an Inhibitory Nucleic Acid Sensor, Unleashes STING, a Cyclic Dinucleotide Receptor that Activates Type I Interferon

Immunity. 2019 Mar 19;50(3):591-599.e6. doi: 10.1016/j.immuni.2019.02.009.

Authors

Xin Li¹, Meng Deng², Alex S Petrucelli¹, Cheng Zhu³, Jinyao Mo⁴, Lu Zhang⁵, Jason W Tam¹, Pablo Ariel⁶, Baoyu Zhao⁷, Song Zhang¹, Hengming Ke³, Pingwei Li⁷, Nikolay V Dokholyan⁸, Joseph A Duncan⁴, Jenny P-Y Ting⁹

Affiliations

¹ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
² Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Oral and Craniofacial Biomedicine PhD Program, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
³ Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.
⁴ Department of Medicine, Division of Infectious Diseases, University of North Carolina, Chapel Hill, NC 27599, USA.
⁵ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27701, USA.
⁶ Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
⁷ Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
⁸ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA; Departments of Pharmacology and Biochemistry and Molecular Biology, Penn State College of Medicine, PA 17033, USA.
⁹ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: jenny_ting@med.unc.edu.

Abstract

Immune suppression is a crucial component of immunoregulation and a subgroup of nucleotide-binding domain (NBD), leucine-rich repeat (LRR)-containing proteins (NLRs) attenuate innate immunity. How this inhibitory function is controlled is unknown. A key question is whether microbial ligands can regulate this inhibition. NLRC3 is a negative regulator that attenuates type I interferon (IFN-I) response by sequestering and attenuating stimulator of interferon genes (STING) activation. Here, we report that NLRC3 binds viral DNA and other nucleic acids through its LRR domain. DNA binding to NLRC3 increases its ATPase activity, and ATP-binding by NLRC3 diminishes its interaction with STING, thus licensing an IFN-I response. This work uncovers a mechanism wherein viral nucleic acid binding releases an inhibitory innate receptor from its target.

Keywords: DNA-binding receptor; NOD-like receptor; STING; TBK1; interferon.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Cell Line
Cell Line, Tumor
DNA, Viral / metabolism*
HEK293 Cells
HeLa Cells
Humans
Immunity, Innate / immunology
Intercellular Signaling Peptides and Proteins / metabolism*
Interferon Type I / metabolism*
Membrane Proteins / metabolism*
Mice
Mice, Inbred C57BL
Nucleic Acids / metabolism
Protein Binding / immunology

Substances

DNA, Viral
Intercellular Signaling Peptides and Proteins
Interferon Type I
Membrane Proteins
NLRC3 protein, mouse
Nucleic Acids
Sting1 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding