OMVs-Delivered Vibrio splendidus sRNA063 OrchestratesPDZRN3-Mediated K48-Linked Polyubiquitination of ATG2 toSuppress Autophagy in Echinoderms

Pathogenic small RNAs (sRNAs) are emerging as cross-kingdom regulators of host immunity, yet the underlying mechanism remains incompletely defined. Here, we identify sRNA063 as a key virulence gene of Vibrio splendidus during the infection of its host, sea cucumber Apostichopus japonicus. sRNA063 is delivered to host coelomocytes via outer membrane vesicles (OMVs) and directly binds the A. japonicus autophagy-related protein 2 (AjATG2), accelerating its degradation through the ubiquitin-proteasome system (UPS) without affecting transcription. Mechanistically, sRNA063 functions as a “molecular scaffold” that recruits the E3 ubiquitin ligase AjPDZRN3, strengthens the AjATG2-AjPDZRN3 binding affinity and suppresses AjPDZRN3 self-ubiquitination. This interaction promotes K48-linked polyubiquitination of AjATG2, thereby impairing autophagy and facilitating intracellular V. splendidus survival. Collectively, these findings uncover a novel cross- kingdom regulation mechanism whereby bacterial sRNAs modulate host protein ubiquitination through scaffolding activity