Selective RNA targeting and regulated signaling by RIG-I is controlled by coordination of RNA and ATP binding

By Megan E. Fitzgerald, David C. Rawling, O. Potapova, Xiaoming Ren, Andrew S. Kohlway, Anna Marie Pyle. 2016

19 citations recorded by the source corpus.

Abstract 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.

Subfields: Immunology, Molecular Biology, Oncology

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. Wenshuai Wang
2. Anna Marie Pyle
3. T. Dickey
4. B. Song

In Molecular Biology

1. Wenshuai Wang
2. T. Dickey
3. B. Song
4. Anna Marie Pyle

In Oncology

1. Wenshuai Wang
2. Anna Marie Pyle

Citations in the corpus

• The RIG-I receptor adopts two different conformations for distinguishing host from viral RNA ligands (2022, positive): “These results demonstrate that rigidifying the RIG-I helicase core through the hydrophobic effect can freeze the protein in the HF conformation, which has low affinity for p3dsRNA ligands in the presence of ATP (Fitzgerald et al., 2017).”
• RNA binding activates RIG-I by releasing an autorepressed signaling domain (2019, background): “However, RIG-I binds OH-SLR14 with moderate affinity (low-nanomolar KD), and OH-SLR14 can activate RIG-I mutants that are deficient in their ability to dissociate from RNA (34).”