LPA maintains innate antiviral immunity in a pro-active state via STK38L-mediated IRF3 Ser303 phosphorylation.

Innate immunity is critical for the early detection and elimination of viral invasion. Extracellular signals are crucial for host resistance; however, how extracellular factors prepare the innate immunity for rapid antiviral response remains elusive. Here, we find that serum deprivation largely restricts the innate antiviral responses to RNA and DNA viruses. When serum is supplied, serine/threonine-protein kinase 38-like (STK38L), induced by serum response factor (SRF), phosphorylates IRF3 at Ser303, which prevents IRF3 from proteasome-mediated degradation in the rest state (non-infected), and ensures that enough IRF3 is called in the primed state (infected). STK38L-deficient mice exhibit compromised innate antiviral responses and elevated viral proliferation and mortality. Moreover, lysophosphatidic acid (LPA) or sphingosine 1-phosphate (S1P), the crucial activators of SRF, rescue immunosuppression caused by serum deprivation. These findings identify the SRF-STK38L-IRF3 axis as a novel mechanism that maintains the host in a pro-active state when not infected, which ensures the rapid immune response against virus. [Display omitted] • Serum deprivation impairs IFN-I signaling by reducing IRF3 Ser303 phosphorylation • Without Ser303 phosphorylation, IRF3 undergo RAUL-mediated proteasomal degradation • STK38L phosphorylates IRF3 at Ser303 and prevents IRF3 degradation • LPA and S1P in serum induce STK38L and ensure rapid innate antiviral response Wang et al. show that the extracellular factors LPA and S1P prepare innate immunity for rapid antiviral response by inducing STK38L expression, which prevents IRF3, a pivotal transcription factor of IFN-I signaling, from proteasomal degradation by phosphorylating IRF3 at Ser303. [ABSTRACT FROM AUTHOR]