The unconventional roles of autophagy-related proteins in infections and immunity

Abstract

Autophagy is a well-known, evolutionary conserved catabolic pathway leading to the degradation of large cytoplasmic elements by the lysosome. Autophagy-related gene (Atg) protein complexes catalyze the formation of double-membrane vesicles called autophagosomes. Bulk cytosol, protein aggregates and damaged organelles but also cytoplasmic microbes such as bacteria, viruses and parasites are sequestered into double-membrane autophagosomes and delivered to the lysosome where they are degraded. Hence, autophagy is essentially induced upon stress situations while also providing protection against intracellular pathogens, adding to the cellular innate immune arsenal. In turn, several pathogens have evolved strategies to evade the autophagy pathway or even manipulate it to sustain their intracellular life cycle. In addition to their traditional role in autophagosome formation, recent finding have attributed novel functions, which are distinct from the classical autophagy pathway, to autophagy-related protein complexes. Autophagy-independent roles of Atg proteins include the maintenance of cellular homeostasis and resistance against invading pathogens. As such, autophagy proteins have been shown to assist and enhance the degradation of dead cells, bacteria and parasites upon their macroendocytic engulfment. It was also demonstrated that a subset of Atg proteins has a direct antiviral function by inhibiting Murine norovirus’ replication complex. Moreover, bone resorption by osteoclasts, innate immune regulation upon double-stranded DNA-triggered signaling and the ER-associated degradation pathway regulation all have in common the requirement of some of the Atg proteins in an autophagosome formation-independent manner. On the other hand, microorganisms, such as coronaviruses, Chlamydia or Brucella, have evolved ways to manipulate and benefit from autophagy-independent functions of autophagy-related proteins in order to ensure the completion of their intracellular life cycle. These novel mechanisms that involve autophagy-related proteins independently from their role during canonical autophagosome formation add to the functional repertoire of Atg proteins and extend the cellular processes in which autophagy proteins are implicated.