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    • Of note core autophagy factors also play an

    2023-01-29

    Of note, core autophagy factors also play an important role during the infection of host cells by another type of picornavirus, namely, echovirus 7. ATG16L1 was found necessary for entry/internalization into Caco-2 polarized epithelial cells because the virus accumulated on the surface of ATG16L1-deficient cells. As to BECLIN 1, ATG12, ATG14 and LC3, they contributed to infection by acting at a level that is upstream of the RNA exit from the KN-93 [100]. Quite surprisingly, UVRAG, known to contribute to both autophagy induction and autophagosome maturation, can behave as another host factor essential for efficient virus entry. Besides BECLIN 1, UVRAG is capable of interaction with the so-called class C vacuolar protein sorting tethering complex that is involved in the functioning of the endosomal pathway. Through Rab7 recruitment, this interaction promotes autophagosome maturation and degradation of endocytic cargoes [101]. However, this interaction also promotes the entry of negative-strand RNA viruses such as VSV and influenza A virus independently of autophagy or IFN-I production. This pro-viral phenomenon, which involves Q-SNARE factors (syntaxin 7, 8, Vti1b), operates through facilitating the access of the endocytosed virus to late endosomes and formation of a fusogenic SNARE complex that recruits the R-SNARE VAMP8 to virus-carrying endosomes and promotes membrane penetration. Concomitantly, VAMP7 that normally contributes to lysosome membrane fusion appears excluded further favoring escape from lysosomal degradation [102]. Again, more work is needed to understand the details of such a remodeling of the endocytic machinery and how common it can be during the entry of enveloped viruses into host cells.
    Non-conventional roles of autophagy factors during viral infection Possibly, early viral infections might get modulated by features that the virions acquired by interacting with the autophagy machinery of the cell they were packaged in. These aspects relate to so-called non-canonical functions of the autophagy machinery. This notion requires us to consider the virus cycle one step back. Apart from their role in the classical autophagy process, factors that execute, or regulate, the autophagic process can substantially modulate cellular events involved in viral infection. Perhaps the best known of such non-conventional function is the LC3-associated phagocytosis (LAP) where the LC3 gets rapidly conjugated to the cytosolic membrane of phagosomes [57], [103]. LC3 recruitment involves the Vps34 complex with no role for ULK1. Depending on the cell type involved, LC3 conjugation might either increase the efficiency of phagosome fusion with lysosomes possibly due to facilitated transport [57], [104] or optimize the encountering of cargoes with component of the lysosomal machinery [72]. Interestingly, LC3-conjugated membranes may also participate in the release of viral particles [105], [106]. The presence of autophagic membranes surrounding assembled viruses has been observed for poliovirus [107] and other picornaviruses which are released in LC3-positive envelopes surrounding multiple virions [108], [109]. Viruses of the herpes family appear to also acquire LC3-positive membranes before exit. Thus, EBV and varicella zoster virus both incorporated LC3-conjugated membrane during their cycle and this event was important for their successful release [110], [111]. Finally, the influenza A virus infection is associated with rerouting of LC3-coupled membranes to the plasma membrane [112], possibly providing budding virions with an abundant supply in membranes. The exact consequences of the presence of LC3 on membranes that envelope assembled viruses are currently poorly understood. It may reflect the use by viruses of the capacity of the autophagy machinery to contribute to unconventional exocytosis. For some of them, it seems to be associated with a more efficient particle release. For others, it could simply reflect the use of the autophagy machinery during envelope production and packaging. Whether enveloped viruses bearing membranes of autophagic origin are endowed with an enhanced capacity to infect host cells remains to be explored. This could well be the case for viruses carrying autophagic membranes with exposed phosphatidylserine content given that phosphatidylserine recognition by scavenger receptors facilitates phagocytic internalization [108], [113]. Thus, features of early viral infection might be influenced by autophagy factors/membranes that were recruited to viral particles in cells they come from.