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Host cell membrane-trafficking pathways are often manipulated by bacterial pathogens to gain cell entry, avoid immune responses, or to obtain nutrients. The 1,369-residue OtDUB protein from the obligate intracellular human pathogenOrientia tsutsugamushibears a deubiquitylase (DUB) and additional domains. Here we show that OtDUB ectopic expression disrupts membrane trafficking through multiple mechanisms. OtDUB binds directly to the clathrin adaptor-protein (AP) complexes AP-1 and AP-2, and the OtDUB 275–675  fragment is sufficient for binding to either complex. To assess the impact of OtDUB interactions with AP-1 and AP-2, we examined  trans- Golgi trafficking and endocytosis, respectively. Endocytosis is reduced by two separate OtDUB fragments: one contains the AP-binding domain (OtDUB 1–675 ), and the other does not (OtDUB 675–1369 ). OtDUB 1–675  disruption of endocytosis requires its ubiquitin-binding capabilities. OtDUB 675–1369  also fragments  trans-  and  cis- Golgi structures. Using a growth-based selection in yeast, we identified viable OtDUB 675–1369  point mutants that also no longer caused Golgi defects in human cells. In parallel, we found OtDUB 675–1369  binds directly to phosphatidylserine, and this lipid binding is lost in the same mutants. Together these results show that OtDUB contains multiple activities capable of modulating membrane trafficking. We discuss how these activities may contribute to  Orientia  infections.

OtDUB from the Human Pathogen Orientia tsutsugamushi Modulates Host Membrane Trafficking by Multiple Mechanisms