Beyond self-eating: The control of nonautophagic functions and signaling pathways by autophagy-related proteins

Cadwell, Ken; Debnath, Jayanta

When antimicrobial immunity is not xenophagy or LAP. Xenophagy, in which an internalized microbe is sequestered in an autophagosome and targeted to the lysosome, is an established form of cell-autonomous defense (Cadwell, 2016) . However, mechanisms by which ATGs restrict intracellular pathogens are sometimes radically different from classic autophagy or LAP. The cytokine IFN-γ inhibits Toxoplasma gondii replication in macrophages by triggering a process referred to as Targeting by AutophaGy proteins (TAG), which requires ATGs involved in LC3 conjugation, but not the lysosome. Instead of promoting acidification, the ATG8 orthologue GAB ARA PL2 (GATE-16) recruits IFN-inducible GTPases to the parasitophorous vacuole where they disrupt the membrane and destroy the replicative niche of T. gondii Park et al., 2016b; Sasai et al., 2017) . A similar mechanism disrupts the membranous structures on which noroviruses replicate (Biering et al., 2017) . Additionally, though xenophagy inhibits Mycobacterium tuberculosis replication in cultured macrophages, experiments using cell type-specific knockout mice revealed a surprising autophagy-independent function of ATG5 in neutrophils. Deletion of ATG5, but not the other ATGs involved in LC3 conjugation, increases the amount of neutrophils that infiltrate and damage the lung during Mycobacterium tuberculosis infection (Kimmey et al., 2015) . As with viruses, bacteria can benefit from selective components of the autophagy machinery. The multimembrane vacuoles that support Brucella abortis replication are generated by ATGs that control PI3 kinase activity (ULK1, Beclin-1, and ATG14), but not ATGs required for LC3 conjugation (ATG7, ATG16L1, ATG5, LC3B, and ATG4B) (Starr et al., 2012) . In addition to these cellautonomous functions of ATGs during infection, nonautophagic ATG functions are important for immune signaling pathways that contribute to multi-cellular immunity, which is discussed in the following section.