Unraveling the Intricacies of Xenophagy: Lessons from Legionella pneumophila.

Autophagy, a conserved eukaryotic process for maintaining cellular homeostasis, plays a crucial role in innate immunity by targeting intracellular pathogens through selective autophagy, known as xenophagy. While xenophagy is vital for pathogen clearance, many intracellular bacteria have evolved sophisticated strategies to avoid or subvert this process. Legionella pneumophila, a Gram-negative intracellular pathogen, manipulates host pathways by an extensive repertoire of effector proteins delivered through its type IV secretion system. This review summarizes the current understanding of xenophagy mechanisms, including cargo recognition, adaptor recruitment, and lysosomal degradation, and describes how L. pneumophila disrupts these steps using effectors such as RavZ, which irreversibly cleaves LC3-II, and the SidE family, which interferes with host ubiquitination by phosphoribosyl ubiquitination. We also discuss additional effectors that perturb autophagy-related processes and the broader insights these bacterial strategies provide into host cell biology. Finally, we highlight future perspectives on leveraging xenophagy research for developing targeted therapies against infectious diseases.