xenophagy

Xenophagy is a selective form of autophagy in which cells target foreign material, particularly intracellular pathogens such as bacteria and viruses, for degradation in lysosomes. As part of cell-autonomous immunity, xenophagy helps limit infection by removing pathogens that have escaped from endosomes or have resisted conventional degradation.

Mechanistically, ubiquitination of microbial surfaces or damaged vesicles marks the target for recognition by autophagy receptors such as p62/SQSTM1, NDP52, and optineurin (OPTN). These receptors bind both ubiquitin chains and LC3 proteins on forming autophagosomes, promoting enclosure of the cargo. The resulting autophagosome fuses with a lysosome, where the pathogen is degraded. Core autophagy genes (for example ATG5, ATG7, Beclin-1) and the ULK1 initiation complex drive the process, while signaling pathways linked to pattern recognition and interferon responses can modulate its activity.

In mammals, xenophagy contributes to defense against intracellular bacteria such as Listeria monocytogenes, Salmonella enterica, and Mycobacterium tuberculosis, as well as certain viruses. Many pathogens have evolved countermeasures to evade xenophagy, including blocking ubiquitination, receptor recruitment, or autophagosome maturation. Clinically, defects in xenophagy-related pathways are associated with heightened susceptibility to infection and with inflammatory or neurodegenerative diseases in some contexts. Ongoing research investigates how xenophagy integrates with other innate immune mechanisms and how it might be leveraged therapeutically.