XopA: a novel type III secretion system effector in Xenorhabdus that modulates host cell responses through apoptosis, autophagy, and immune evasion

ABSTRACT The type III secretion system (T3SS) of bacterial pathogens plays an essential role in infection and colonization processes. T3S effectors (T3SEs) are pivotal in mediating these interactions and their mechanisms of action. This study delves into the functional mechanisms of XopA, the first T3SE identified in the bacterium Xenorhabdus , which belongs to the YopJ family. XopA demonstrates cytotoxicity akin to other YopJ family members and possesses virulence determinants capable of inducing both apoptosis and autophagy. Notably, our findings reveal a complex regulatory network between XopA-induced apoptosis and autophagy. Moreover, XopA modulates the host cell’s global and inflammatory responses by targeting tubulin, thereby affecting cytoskeletal dynamics and the secretion of extracellular vesicles (EVs). The acetylation activity characteristic of the YopJ family effectors is significantly altered in HeLa cells upon XopA action, highlighting its role in post-translational modifications. Collectively, this study elucidates the multifaceted functional mechanisms of XopA, which will undoubtedly be beneficial for a better understanding of the molecular mechanisms of Xenorhabdus pathogenesis. IMPORTANCE This study reports the groundbreaking discovery of XopA as the first type III secretion system effectors (T3SE) identified in Xenorhabdus bacteria. By demonstrating its unique ability to concurrently induce host cell apoptosis and autophagy, execute lysine acetyltransferase activity to suppress inflammatory signaling, and disrupt cytoskeletal dynamics to inhibit extracellular vesicle secretion, this work reveals a sophisticated multifunctional virulence mechanism. These findings significantly advance our understanding of bacterial pathogenesis, providing crucial insights into how T3SEs manipulate host cell processes and evade immune responses, thereby establishing a new frontier in host-pathogen interaction research.