Many negative-sense RNA viruses, including measles virus (MeV), are thought to carry out much of their viral replication in cytoplasmic membraneless foci known as inclusion bodies (IBs). The mechanisms by which IBs facilitate efficient viral replication remain largely unknown but may involve an intricate network of regulation at the host-virus interface. Viruses are able to modulate such interactions by a variety of strategies including adaptation of their genomes and "hijacking" of host
proteins. The latter possibility broadens the molecular reservoir available for a virus to enhance its replication and/or antagonize host
antiviral responses. Here, we show that the cellular 5'-3'
exoribonuclease, XRN1, is a host
protein hijacked by MeV. We found that upon MeV
infection, XRN1 is translocated to cytoplasmic IBs where it acts in a proviral manner by preventing the accumulation of
double-stranded RNA (dsRNA) within the IBs. This leads to the suppression of the dsRNA-induced innate immune responses mediated via the
protein kinase R (PKR)-integrated stress response (ISR) pathway. IMPORTANCE Measles virus remains a major global health threat due to its high transmissibility and significant morbidity in children and immunocompromised individuals. Although there is an effective
vaccine against
MeV, a large population in the world remains without access to the
vaccine, contributing to more than 7,000,000
measles cases and 60,000
measles deaths in 2020 (CDC). For negative-sense RNA viruses including MeV, one active research area is the exploration of virus-host interactions occurring at cytoplasmic IBs where viral replication takes place. In this study we present evidence suggesting a model in which MeV IBs antagonize host innate immunity by recruiting XRN1 to reduce dsRNA accumulation and subsequent PKR
kinase activation/ISR induction. In the absence of XRN1, the increased dsRNA level acts as a potent activator of the
antiviral PKR/ISR pathway leading to suppression of global cap-dependent mRNA translation and inhibition of viral replication.