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  • br Autophagy and antiviral innate immunity signaling br Vira

    2023-11-20


    Autophagy and antiviral innate immunity signaling
    Viral manipulation of autophagy interfering with IFN-I synthesis We have seen that autophagy factors can down-regulate the production of IFN-I induced by RLR engagement during viral infection. In fibroblasts and epithelial cells, there exists constitutive interactions between the ATG5–ATG12 complex and RIG-I or its signaling adaptor IPS-1. VSV infection further strengthens these interactions causing a diminished production of the IFN-I production normally triggered by RIG-I activation [83]. RIG-I signaling can also be down-modulated by autophagy in murine embryonic fibroblasts and macrophages. This regulation relies on the elimination of reactive oxygen species that contribute to IPS-1 adaptor expression and promote RIG-I signaling-dependent IFN-I production in EGTA infected with VSV [84]. In hepatoma cells infected with HCV, the so-called unfolded protein response induces an autophagic activity that promotes viral RNA replication [85]. This pro-viral effect of autophagy involves inhibition EGTA of the IFN-I production induced by the RIG-I-mediated sensing of viral components. Interfering with unfolded protein response or autophagy can restore IFN-I production. IFN-I production can also be influenced by the progression of the autophagy flux. For instance, blocking the maturation of autophagosomes promotes activation of the IFNβ promoter, while activation of the flux tends to diminish it. The unperturbed formation of autolysosomes during flux progression appears therefore as a negative regulator of IFN-I production. Along with the production of mitochondrial reactive oxygen species, enhanced IFN-I production is easily observed upon HCV infection of cells that are deficient in autophagy [86]. Thus, the induction of autophagy by virus such as HCV can be a way to limit IFN-I production by host cells. In a comparable way, during VSV infection, the mitochondrial factor TUFM interferes with IFNβ production through interaction with the IPS-1 interacting/inhibitory protein NLRX1. Interestingly, TUFM can also be an interacting partner for the ATG5–ATG12 complex and thereby an autophagy inducer [87]. Whether alteration of IFN-I production can be a direct consequence of autophagy activation through TUFM remains, however, to be clarified. The mitochondrial factor MFN2, which can be involved in the contribution of mitochondrial membranes to autophagosome formation [88], also interacts with IPS-1 to inhibit IFNβ production, facilitating the replication of viruses such as VSV [89]. Another component that regulates IFN-I synthesis through interaction with IPS-1 during viral infection is the cytochrome C oxydase subunit COX5B. By recruiting ATG5, COX5B interferes with the aggregation of IPS-1 that it required for its antiviral function [90]. Finally, HSV-1 was found capable of inhibiting both anti-viral autophagy and innate immune responses through the targeting of PKR [91], indicating that viruses can in some instance alter both IFN-I synthesis and autophagy. Thus, viruses evolved several means to interfere with the crosstalk between autophagy and IFN-I inducing pathways. Interestingly, the manipulation of mitochondrial factors able to regulate either autophagy or IFN-I production might represent a frequent strategy used by various viruses to optimize their infectious potential.
    Viral manipulation of autophagy interfering with inflammatory responses As mentioned above, activation of inflammasomes can be an important part of innate immune responses of host cells to invading viruses, in particular through the secretion of cytokines of the IL-1β/IL-18 family. Interestingly, while autophagy inhibition favors IL-1β production, the activation of autophagy rather inhibits the activity of the inflammasome [79]. Hence, autophagy is a potent negative regulator of inflammatory responses. Besides down-regulation through inflammasome regulation, autophagy can also inhibit the production of IL-1β by limiting IL1β transcription level [92]. Viruses can in fact escape inflammatory responses through the manipulation of autophagy. For example, the murine cytomegalovirus (MCMV) uses its M45 protein to triggers the autophagic degradation of NEMO, a regulator of NF-κB [93]. This targeting interferes with NF-κB activation and the related production of inflammatory cytokines. In macrophages, activation of the AIM2 or NLRP3 inflammasomes via engagement of the G protein called RalB induces autophagy. On the other hand, the inflammasome component ASC can be targeted to autophagic degradation by p62 upon ubiquitination leading to the dampening of inflammasome activation. The influenza A virus is capable of concomitantly inhibiting autophagy and activating the inflammasome. This involves its M2 factor that can function as a proton channel. During infection, the engagement of TLR7 by agonist ligands activates pro-IL-1β transcription that translates into efficient production of IL-1β since M2 can activate NLRP3. In addition, the proton channel activity of M2 further promotes the activation of NLRP3 by exporting protons from the Golgi apparatus [94]. Of note, the M2 protein also has the capacity to inhibit the maturation of autophagosomes [95]. Whether this inhibition influences inflammasome activation is unknown. Another important pro-inflammatory factor produced by virally infected cells, in particular DCs and macrophages, is tumor necrosis factor (TNF)-α. In DCs infected with HIV-1, autophagy is rapidly affected. This inhibition, which involves the envelope protein, the CD4 co-receptor and the activation of mTOR, benefits to the virus by protecting it from degradation. Under conditions of perturbed autophagy, the production of TNF-α normally induced upon TLR engagement is lowered and HIV-1 rapidly accumulated in amphisomes which are organelles derived from the fusion of endosome/phagosome with autophagosomes [96]. The efficient interference of HIV-1 with the maturation of virus-carrying amphisomes through inhibition of autophagy suggests that, in DCs, amphisomes may be efficient at promoting the degradation of virions. The molecular events involved in the rapid formation of HVI-1-containing amphisomes in human DCs remain to be characterized.