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Abstract
Porcine reproductive and respiratory syndrome virus (PRRSV) causes porcine reproductive and respiratory syndrome (PRRS), which is currently insufficiently controlled. RACK1 (receptor of activated protein C kinase 1) was first identified as a receptor for protein kinase C, with increasing evidence showing that the functionally conserved RACK1 plays important roles in cancer development, NF-κB activation and various virus infections. However, the roles of RACK1 during PRRSV infection in Marc-145 cells have not been described yet. Here we demonstrated that infection of Marc-145 cells with the highly pathogenic PRRSV strain YN-1 from our lab led to activation of NF-κB and upregulation of RACK1 expression. The siRNA knockdown of RACK1 inhibited PRRSV replication in Marc-145 cells, abrogated NF-κB activation induced by PRRSV infection and reduced the viral titer. Furthermore, knockdown of RACK1 could inhibit an ongoing PRRSV infection. We found that RACK1 is highly conserved across different species based on the phylogenetic analysis of mRNA and deduced amino acid sequences. Taken together, RACK1 plays an indispensable role for PRRSV replication in Marc-145 cells and NF-κB activation. The results would advance our further understanding of the molecular mechanisms underlying PRRSV infection in swine and indicate RACK1 as a promising potential therapeutic target.
Highlights
Porcine reproductive and respiratory syndrome (PRRS) is characterized by respiratory disorders in piglets and reproductive failure in sows[1]
We further show that siRNA knockdown of RACK1 in Marc-145 cells downregulates Porcine reproductive and respiratory syndrome virus (PRRSV) replication, abrogates NF-κB activation induced by PRRSV infection and reduces the viral titer
At least seven cellular molecules have been described as putative receptors for PRRSV, including heparan sulfate, vimentin, CD151, sialoadhesin (CD169), dendritic cell-specific intercellular adhesion melecule-3-grabbing non-integrin (DC-SIGN; CD209), vimentin and CD16334,35
Summary
Porcine reproductive and respiratory syndrome (PRRS) is characterized by respiratory disorders in piglets and reproductive failure in sows[1]. An earlier study, using the yeast two-hybrid (Y2H) system, showed that RACK1 (receptor of activated protein C kinase 1) might interact with the PRRSV protein NSP96. The sequence and function of RACK1 is highly conserved across evolutionarily distant species (from human to fly) It plays vital roles at different phases of various virus infections[14]. RACK1 plays an anti-apoptotic role during infectious bursal disease virus (IBDV) infection via interaction with VDAC2 and VP5. It suggests that VP5 sequesters RACK1 and VDAC2 in the apoptosis-inducing process[21]. RACK1 was screened with CSFV E2 as bait protein by yeast two-hybrid from porcine alveolar macrophages (PAM cells) expression library, which was further confirmed by co-transformation, GST pull-down and laser confocal assays[24]. We further show that siRNA knockdown of RACK1 in Marc-145 cells downregulates PRRSV replication, abrogates NF-κB activation induced by PRRSV infection and reduces the viral titer
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