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  • br Viral manipulation of host

    2023-01-10


    Viral manipulation of host factors to oppose anti-viral autophagy To escape or manipulate autophagy, some viruses developed strategies that are based on the recruitment of host-cell endogenous factors. The non-enveloped double-stranded DNA virus adenovirus is rapidly endocytosed after attachment. The ensuing structural modifications of the Docetaxel expose the internal capsid protein VI (PVI) that has the capacity to fragment the endosomal membrane and give the virus access to the cytosol. This allows the virus to escape degradation associated with the endocytic pathway. Within PVI, a particular PPxY motif interacts with WW domains of host factors such as the HECT E3 ubiquitin ligases Nedd4.1/.2. The PPxY–Nedd4.2 interaction is crucial for endosomal escape. In fact, the membrane fragmentation induces an autophagic response by host cells. The ruptured endosome is detected by Galectin 3, 8 and 9 and is associated with formation of autophagosomes at the site of membrane fragmentation. However, adenovirus is not restricted by autophagic responses [97]. Interestingly, a mutant adenovirus with a PVI factor devoid of the PPxY motif could fragment the endosomal membrane but displayed poor endosomal escape. This phenotype was reverted upon autophagy inhibition, indicating that the PPxY motif is involved in counteracting autophagic response to wild-type adenovirus. Reversion to escape was also seen upon depletion of Galectin 8 (but not 3/9). Thus, Galectin 8 connects virally damaged endosomes to the autophagy machinery. Although localized at the membrane fragmentation site, neither NDP52 nor p62 was required for the autophagic degradation of the mutant virus, suggesting that other autophagy factors can recruit the autophagy machinery to altered membranes [97] (Fig. 2D).It appears that the resistance to autophagy involves the capacity of the virus to interfere with the process of autophagosome maturation. This effect also involves the PPxY motif of protein VI, possibly through the sequestration of Nedd4.2 which may contribute to autophagosome closure and maturation. At the same time adenovirus opposes sequestration into autophagosomes, it takes advantage of the autophagy machinery to deliver its genome to the nucleus of host cells. Consistent with this notion was the finding that in the absence of ATG5, the capsids are poorly exported from the damaged endosomes and their transport to the nuclear periphery via the microtubule organizing center (MTOC) is inefficient [97]. Possibly, the autophagy machinery could promote the recruitment of molecular motors (such as Dynein) to ruptured endosome and assist capsid exit from endosomes. As LC3 colocalized with capsids retrogradly moving toward the nucleus, it is possible that LC3 gets recruited to capsids and participate in capsid–dynein interaction [97]. This effect would be reminiscent of the contribution of LC3 to microtubule-based trafficking of autophagosomes [98]. Thus, during entry, the adenovirus benefits from autophagy and at the same time uses the specialized PVI factor to avoid restriction by autophagy. Picornaviruses such as poliovirus or coxsackievirus B1 are other non-enveloped viruses that also take advantage of cellular factors early during infection to counteract autophagic defenses. After endocytosis, conformational rearrangements of the picornavirus capsid protein correlate with induction of a pore within the endosomal membrane that is used to introduce the viral RNA into the cytosol for translation. The host lipid modifying enzyme PLA2G16 was found to be crucial for successful virus entry since cells lacking PLA2G16 were resistant to infection and Pla2g16-deficient mice could survive to viral titers that are lethal for their wild-type counterparts. The recruitment of enzymatically active PLA2G16 is in fact a key step that couples endosome fragmentation with productive viral RNA translocation. A screen for genes able to restore viral infection in PLA2G16-deficient cells revealed several autophagy-related genes including Galectin 8. Both Galectin 8 and PLA2G16 accumulated at the site of pore formation in infected cells, but in an independent manner. It appears that PLA2G16 promotes RNA translocation by interfering with Galectin 8 local positioning, thereby protecting viral RNAs from Galectin 8-associated autophagic responses [99] (Fig. 2D). Thus, besides known mechanisms such as ribonuclease activities, autophagy represents that another line of defense cells can oppose to picornavirus RNA entry, and the in situ recruitment of the cellular factor PLA2G16 is a viral strategy to oppose this autophagic obstacle. In line with this model, deficiency in key autophagy factors such as ATG7 and ATG16L1 restored the susceptibility of PLA2G16-deficient cells to picornavirus infection. Further work is needed to elucidate the precise role of PLA2G16 during infection.