PCV2 targets cGAS to inhibit type I interferon induction to promote other DNA virus infection

Abstract

Viruses use diverse strategies to impair the antiviral immunity of host in order to promote infection and pathogenesis. Herein, we found that PCV2 infection promotes the infection of DNA viruses through inhibiting IFN-β induction in vivo and in vitro. In the early phase of infection, PCV2 promotes the phosphorylation of cGAS at S278 via activation of PI3K/Akt signaling, which directly silences the catalytic activity of cGAS. Subsequently, phosphorylation of cGAS at S278 can facilitate the K48-linked poly-ubiquitination of cGAS at K389, which can been served as a signal for recognizing by the ubiquitin-binding domain of histone deacetylase 6 (HDAC6), to promote the translocation of K48-ubiquitinated-cGAS from cytosol to autolysosome depending on the deacetylase activity of HDAC6, thereby eventually resulting in a markedly increased cGAS degradation in PCV2 infection-induced autophagic cells relative to Earle’s Balanced Salt Solution (EBSS)-induced autophagic cells (a typical starving autophagy). Importantly, we found that PCV2 Cap and its binding protein gC1qR act as predominant regulators to promote porcine cGAS phosphorylation and HDAC6 activation through mediating PI3K/AKT signaling and PKCδ signaling activation. Based on this finding, gC1qR-binding activity deficient PCV2 mutant (PCV2RmA) indeed show a weakened inhibitory effect on IFN-β induction and a weaker boost effect for other DNA viruses infection compared to wild-type PCV2. Collectively, our findings illuminate a systematic regulation mechanism by which porcine circovirus counteracts the cGAS-STING signaling pathway to inhibit the type I interferon induction and promote DNA virus infection, and identify gC1qR as an important regulator for the immunosuppression induced by PCV2.

Canine Circovirus Suppresses the Type I Interferon Response and Protein Expression but Promotes CPV-2 Replication

“…Studies have shown that some circoviruses affect the host interferon response [ 21 ]. The innate immune response is the first line of defense of a host.…”

Advances in Crosstalk between Porcine Circoviruses and Host

“…During the infection, the viral Cap can inhibit ubiquitin-mediated proteasomal degradation of cellular C1QBP, thus further enhancing the phagocytic activity of PAM through the PI3K pathway [ 127 ]. Furthermore, the interaction of viral Cap and host C1QBP also promotes phosphorylation of cyclic dinucleotide GMP-AMP (cGAMP) synthase (cGAS) via PI3K/Akt and PKCδ signal pathways [ 128 ]. Then, the release of cGAMP is enhanced, which binds to the Stimulator of Interferon Genes (STING) and induces dimerization and translocation of STING into the nucleus, resulting in an enhancement of IFN-β production [ 128 , 129 ].…”

“…Furthermore, the interaction of viral Cap and host C1QBP also promotes phosphorylation of cyclic dinucleotide GMP-AMP (cGAMP) synthase (cGAS) via PI3K/Akt and PKCδ signal pathways [ 128 ]. Then, the release of cGAMP is enhanced, which binds to the Stimulator of Interferon Genes (STING) and induces dimerization and translocation of STING into the nucleus, resulting in an enhancement of IFN-β production [ 128 , 129 ]. Additionally, PCV2 infection also activated retinoic acid-inducible gene I (RIG-1, DDX58), melanoma differentiation-associated protein 5 (MDA-5), and mitochondria antiviral-signaling protein (MAVS), which then led to the enhancement of downstream molecules, such as IFN regulatory factor 3 (IRF3) and IRF7, and thereby the expression of IFN-β gene was increased [ 130 , 131 ].…”

“…Additionally, K389 residue of phosphorylated cGAS was modified by K48-linked poly-ubiquitination and recognized by the ubiquitin-binding domain of histone deacetylase 6 (HDAC6), and then cGAS was degraded in autolysosome [ 128 ]. Moreover, the interaction between antiviral proteins GTPase-activating protein-(SH3 domain)-binding protein 1 (G3BP1) and cGAS can be inhibited by direct interaction between PCV3 Cap and G3BP1 [ 133 ].…”

Targeting Selective Autophagy as a Therapeutic Strategy for Viral Infectious Diseases

“…However, recent studies revealed several viruses are capable to subvert selective autophagy to counteract IFN signaling cascade by promoting autophagic degradation of key components in IFN pathway. To attenuate the activation of IFN signaling, porcine circoviruses type 2 (PCV2) could induce phosphorylation of cGAS at S278 via activation of PI3K/Akt signaling which abolishes cGAS’s catalytic activity, and subsequently promote the K48-linked ubiquitination of cGAS, which is targeted by HDAC6 and delivered to autolysosome for degradation ( Wang Z. et al, 2021 ). In addition to degrade viral receptors, several viruses promote the autophagic degradation of adaptor proteins in IFN pathway to block signal amplification.…”