Functions of MAP3Ks in antiviral immunity.

Immune signal transduction is crucial to the body's defense against viral infection. Recognition of pathogen-associated molecular patterns by pattern recognition receptors (PRRs) activates the transcription of interferon regulators and nuclear factor-κB (NF-κB); this promotes the release of interferons and inflammatory factors. Efficient regulation of type I interferon and NF-κB signaling by members of the mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) family plays an important role in antiviral immunity. Elucidating the specific roles of MAP3K activation during viral infection is essential to develop effective antiviral therapies. In this review, we outline the specific regulatory mechanisms of MAP3Ks in antiviral immunity and discuss the feasibility of targeting MAP3Ks for the treatment of virus-induced diseases.

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.