Abstract
Cytoplasmic pattern recognition receptors detect non-self RNAs during virus infections and initiate antiviral signaling. One receptor, MDA5, possesses essential signaling domains, but weak RNA binding. A second receptor, LGP2, rapidly detects diverse dsRNA species, but lacks signaling domains. Accumulating evidence suggests LGP2 and MDA5 work together to detect viral RNA and generate a complete antiviral response, but the basis for their cooperation has been elusive. Experiments presented here address this gap in antiviral signaling, revealing that LGP2 assists MDA5-RNA interactions leading to enhanced MDA5-mediated antiviral signaling. LGP2 increases the initial rate of MDA5-RNA interaction and regulates MDA5 filament assembly, resulting in the formation of more numerous, shorter MDA5 filaments that are shown to generate equivalent or greater signaling activity invivo than the longer filaments containing only MDA5. These findings provide a mechanism for LGP2 coactivation of MDA5 and a biological context for MDA5-RNA filaments in antiviral responses.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 771-781 |
| Number of pages | 11 |
| Journal | Molecular cell |
| Volume | 55 |
| Issue number | 5 |
| DOIs | |
| State | Published - 2014 |
Funding
We are grateful to John Marko for assistance with single-molecule experiments and members of the Horvath lab for helpful comments on this work and manuscript. Research on RLRs in the Horvath lab was supported by NIH grants AI073919 and AI50707 to C.M.H. A.M.B. was supported by a predoctoral fellowship from the NIH Cellular and Molecular Basis of Disease Training Grant T32GM008061. G.P.L. and R.A.L. are a Research Specialist and an Investigator, respectively, of the Howard Hughes Medical Institute.
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology