A novel proviral mechanism for the ISG, Shiftless, during human coronavirus infection
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As highly pathogenic human coronaviruses continue to emerge from zoonotic sources, understanding how host intrinsic immune responses control infection is critical for preventing severe disease. The interferon (IFN) pathway induces antiviral effectors, including the interferon-stimulated gene (ISG) Shiftless (SHFL), which restricts-1 programmed ribosomal frameshifting during SARS-CoV-2 infection. Here, we investigate a novel proviral mechanism for SHFL using loss-of-function and gain-of-function approaches. Despite its established antiviral activity, SHFL enhanced infection by SARS-CoV-2 and the seasonal coronavirus HCoV-229E by increasing cellular susceptibility to infection. SHFL further promoted coronavirus infection by reducing cellular sensitivity to IFNα, potentially through modulation of JAK/STAT signaling. Finally, we demonstrate that SHFL-mediated enhancement of baseline viral susceptibility is partially dependent on the domain previously implicated in its antiviral inhibition of-1 programmed ribosomal frameshifting. In contrast, SHFL-mediated regulation of IFN signaling is independent of this domain. Together, these findings establish SHFL as a dual-function ISG with distinct proviral and antiviral activities, highlighting the complex roles of innate immune effectors during coronavirus infection.
Importance
Highly pathogenic human coronaviruses have emerged three times since 2002, and spillovers are likely to continue as human contact with animal habitats increases. Against a novel pathogen, the innate immune response is the host’s first line of defense, and interferon-stimulated genes (ISGs) are its main effectors. Growing evidence suggests that although ISGs are canonically antiviral, viruses may co-opt them for proviral functions. Here we describe a novel, proviral function of the ISG Shiftless (SHFL) during infection by SARS-CoV-2 and the seasonal coronavirus HCoV-229E. Our findings show that a gene induced by IFN is not necessarily an antiviral factor. For human coronaviruses, the induction of SHFL works in the virus’s favor initially but may play an antiviral role downstream. Knowing which ISGs have dual functions, and in which cells, is a prerequisite for interpreting context-dependent IFN responses and for understanding the balance between host defense and viral persistence.
