Activation of interferon regulatory factor 3 upregulates endogenous SAMHD1 expression is vital for antiviral innate immunity

The sterile alpha motif and HD domain 1 (SAMHD1) protein has been identified as a novel innate immunity restriction factor that inhibits HIV-1 infection in myeloid cells, and is a type I interferon (IFN) inducible restriction factor. Previous study showed that overexpression of porcine SAMHD1 efficiently blocked highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) replication in MARC-145 cells, and SAMHD1 is activated in target cells (porcine alveolar macrophages, PAMs) after infection of PRRSV. The underlying mechanisms of SAMHD1 transcriptional regulation by virus infection remain elusive.

Here, we used porcine reproductive and respiratory syndrome virus (PRRSV) and Newcastle disease virus (NDV) infection as models and show that inducing SAMHD1 upregulation is part of an early intrinsic immune response via TLR3 and RIG-I/MDA5 agonists that ultimately induce the nuclear translocation of the interferon regulation factor 3 (IRF3) protein.

IRF3 plays a major role in upregulating endogenous SAMHD1 expression in a mechanism that is independent of the classical IFN-induced JAKSTAT pathway. Both overexpression and activation of IRF3 enhanced the SAMHD1 promoter luciferase activity and IRF3 activation was necessary for upregulating SAMHD1 expression in type I IFN cascade. We also show that the SAMHD1 promoter is a direct target of IRF3 and an IRF3 binding site is sufficient to render this promoter responsive to stimulation.

Collectively, these findings indicate that upregulation of endogenous SAMHD1 expression is connected to the phosphorylation and nuclear translocation of IRF3 and we suggest that type I IFN induction and induced SAMHD1 expression are coordinated.

Disclosure of Interest: None Declared.