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dc.contributor.authorVoss, O.H.
dc.contributor.authorGillespie, J.J.
dc.contributor.authorLehman, S.S.
dc.contributor.authorRennoll, S.A.
dc.contributor.authorBeier-Sexton, M.
dc.contributor.authorRahman, M.S.
dc.contributor.authorAzad, A.F.
dc.date.accessioned2020-06-30T18:46:26Z
dc.date.available2020-06-30T18:46:26Z
dc.date.issued2020
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85086686215&doi=10.1128%2fmBio.00820-20&partnerID=40&md5=54baf75484938dca027a9ad124e84a40
dc.identifier.urihttp://hdl.handle.net/10713/13185
dc.description.abstractTo establish a habitable intracellular niche, various pathogenic bacteria secrete effectors that target intracellular trafficking and modulate phosphoinositide (PI) metabolism. Murine typhus, caused by the obligate intracellular bacterium Rickettsia typhi, remains a severe disease in humans. However, the mechanisms by which R. typhi effector molecules contribute to internalization by induced phagocytosis and subsequent phagosomal escape into the cytosol to facilitate the intracellular growth of the bacteria remain ill-defined. Here, we characterize a new molecule, Risk1, as a phosphatidylinositol 3-kinase (PI3K) secreted effector and the first bacterial secretory kinase with both class I and III PI3K activities. Inactivation of Risk1 PI3K activities reduced the phosphorylation of phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-trisphosphate within the host, which consequently diminished host colonization by R. typhi During infection, Risk1 targets the Rab5-EEA1-phosphatidylinositol 3-phosphate [PI(3)P] signaling axis to promote bacterial phagosomal escape. Subsequently, R. typhi undergoes ubiquitination and induces host autophagy; however, maturation to autolysosomes is subverted to support intracellular growth. Intriguingly, only enzymatically active Risk1 binds the Beclin-1 core complex and contributes to R. typhi-induced autophagosome formation. In sum, our data suggest that Risk1, with dual class I and class III PI3K activities, alters host PI metabolism and consequently subverts intracellular trafficking to facilitate intracellular growth of R. typhiIMPORTANCERickettsia species are Gram-negative obligate intracellular bacteria that infect a wide range of eukaryotes and vertebrates. In particular, human body louse-borne Rickettsia prowazekii and flea-borne Rickettsia typhi have historically plagued humankind and continue to reemerge globally. The unavailability of vaccines and limited effectiveness of antibiotics late in infection place lethality rates up to 30%, highlighting the need to elucidate the mechanisms of Rickettsia pathogenicity in greater detail. Here, we characterize a new effector, Risk1, as a secreted phosphatidylinositol 3-kinase (PI3K) with unique dual class I and class III activities. Risk1 is required for host colonization, and its vacuolar phosphatidylinositol 3-phosphate generation modulates endosomal trafficking to arrest autophagosomal maturation. Collectively, Risk1 facilitates R. typhi growth by altering phosphoinositide metabolism and subverting intracellular trafficking. Copyright 2020 Voss et al.en_US
dc.description.urihttps://doi.org/10.1128/mBio.00820-20en_US
dc.language.isoen_USen_US
dc.publisherAmerican Society for Microbiologyen_US
dc.relation.ispartofmBio
dc.subjectautophagosomal maturationen_US
dc.subjectbacterial escapeen_US
dc.subjectBeclin-1en_US
dc.subjectEEA1en_US
dc.subjectendosomal traffickingen_US
dc.subjectLC3ben_US
dc.subjectphagosome escapeen_US
dc.subjectphosphoinositide metabolismen_US
dc.subjectR. typhien_US
dc.subjectRab5en_US
dc.subjectRisk1en_US
dc.subjectubiquitinen_US
dc.titleRisk1, a Phosphatidylinositol 3-Kinase Effector, Promotes Rickettsia typhi Intracellular Survivalen_US
dc.typeArticleen_US
dc.identifier.doi10.1128/mBio.00820-20
dc.identifier.pmid32546622


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