Selective RNA targeting and regulated signaling by RIG-I is controlled by coordination of RNA and ATP binding.
RIG-I is an innate immune receptor that detects and responds to infection by deadly RNA viruses such as influenza, and Hepatitis C. In the cytoplasm, RIG-I is faced with a difficult challenge: it must sensitively detect viral RNA while ignoring the abundance of host RNA. It has been suggested that RIG-I has a ‘proof-reading’ mechanism for rejecting host RNA targets, and that disruptions of this selectivity filter give rise to autoimmune diseases. Here, we directly monitor RNA proof-reading by RIG-I and we show that it is controlled by a set of conserved amino acids that couple RNA and ATP binding to the protein (Motif III). Mutations of this motif directly modulate proof-reading by eliminating or enhancing selectivity for viral RNA, with major implications for autoimmune disease and cancer. More broadly, the results provide a physical explanation for the ATP-gated behavior of SF2 RNA helicases and receptor proteins.
Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA.|Howard Hughes Medical Institute, Chevy Chase, MD, USA.
Megan E
ME
Fitzgerald
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
David C
DC
Rawling
Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA.
Olga
O
Potapova
Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA.|Howard Hughes Medical Institute, Chevy Chase, MD, USA.
Xiaoming
X
Ren
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
Andrew
A
Kohlway
Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA.|Howard Hughes Medical Institute, Chevy Chase, MD, USA.
Anna Marie
AM
Pyle
D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D019943:Amino Acid Substitution; D015551:Autoimmunity; D001665:Binding Sites / Q000235:genetics; D000071457:DEAD Box Protein 58 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D012313:RNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012328:RNA Viruses / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity; D012367:RNA, Viral / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic; D051192:Receptors, Pattern Recognition / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D012367:RNA, Viral; D011971:Receptors, Immunologic; D051192:Receptors, Pattern Recognition; D012313:RNA; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58