The RNA binding protein La/SS-B promotes RIG-I-mediated type I and type III IFN responses following Sendai viral infection

Rebecca Mahony,Lindsay Broadbent,Caroline A Jefferies,Ultan F Power,Jacen S Maier-Moore

doi:10.1038/s41598-017-15197-9

Abstract

La/SS-B (or La) is a 48 kDa RNA-binding protein and an autoantigen in autoimmune disorders such as systemic lupus erythematosus (SLE) and Sjögren’s syndrome (SS). La involvement in regulating the type I interferon (IFN) response is controversial - acting through both positive and negative regulatory mechanisms; inhibiting the IFN response and enhancing viral growth, or directly inhibiting viral replication. We therefore sought to clarify how La regulates IFN production in response to viral infection. ShRNA knockdown of La in HEK 293 T cells increased Sendai virus infection efficiency, decreased IFN-β, IFN-λ1, and interferon-stimulated chemokine gene expression. In addition, knockdown attenuated CCL-5 and IFN-λ1 secretion. Thus, La has a positive role in enhancing type I and type III IFN production. Mechanistically, we show that La directly binds RIG-I and have mapped this interaction to the CARD domains of RIG-I and the N terminal domain of La. In addition, we showed that this interaction is induced following RIG-I activation and that overexpression of La enhances RIG-I-ligand binding. Together, our results demonstrate a novel role for La in mediating RIG-I-driven responses downstream of viral RNA detection, ultimately leading to enhanced type I and III IFN production and positive regulation of the anti-viral response.

Highlights

Activation, leading to the inhibition of transcription and translation of viral proteins[17,18], along with induction and synthesis of MHC class I expression
A number of virulence factors have been mapped to either structural proteins associated with differential virus attachment and entry into host cells, or non-structural proteins implicated in immune modulation that includes antagonism of interferon signalling[47,48,49,50]
With this work we have demonstrated a novel interaction between La/ SSB (La) and RIG-I, which results in enhanced RIG-I-RNA association

Summary

Introduction

Activation, leading to the inhibition of transcription and translation of viral proteins[17,18], along with induction and synthesis of MHC class I expression This makes the cell more susceptible to CD8+ cytotoxic T cells[19,20], activates NK cells which selectively kill virus-infected cells[21,22], and leads to maturation of DCs23 and B cell responses[20,24]. La is required for an optimum IFN response to Sendai virus infection by binding to the anti-viral RIG-I receptor and promoting its interaction with its cognate ligand

Methods

Results

Conclusion