Risk1, a Phosphatidylinositol 3-Kinase Effector, Promotes Rickettsia typhi Intracellular Survival
Date
2020Journal
mBioPublisher
American Society for MicrobiologyType
Article
Metadata
Show full item recordAbstract
To 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.Keyword
autophagosomal maturationbacterial escape
Beclin-1
EEA1
endosomal trafficking
LC3b
phagosome escape
phosphoinositide metabolism
R. typhi
Rab5
Risk1
ubiquitin
Identifier to cite or link to this item
https://www.scopus.com/inward/record.uri?eid=2-s2.0-85086686215&doi=10.1128%2fmBio.00820-20&partnerID=40&md5=54baf75484938dca027a9ad124e84a40; http://hdl.handle.net/10713/13185ae974a485f413a2113503eed53cd6c53
10.1128/mBio.00820-20
Scopus Count
Collections
Related articles
- RalF-Mediated Activation of Arf6 Controls Rickettsia typhi Invasion by Co-Opting Phosphoinositol Metabolism.
- Authors: Rennoll-Bankert KE, Rahman MS, Guillotte ML, Lehman SS, Beier-Sexton M, Gillespie JJ, Azad AF
- Issue date: 2016 Dec
- A Phosphatidylinositol 3-Kinase Effector Alters Phagosomal Maturation to Promote Intracellular Growth of Francisella.
- Authors: Ledvina HE, Kelly KA, Eshraghi A, Plemel RL, Peterson SB, Lee B, Steele S, Adler M, Kawula TH, Merz AJ, Skerrett SJ, Celli J, Mougous JD
- Issue date: 2018 Aug 8
- Role of phosphatidylinositol 3-kinase and Rab5 effectors in phagosomal biogenesis and mycobacterial phagosome maturation arrest.
- Authors: Fratti RA, Backer JM, Gruenberg J, Corvera S, Deretic V
- Issue date: 2001 Aug 6
- Which Way In? The RalF Arf-GEF Orchestrates Rickettsia Host Cell Invasion.
- Authors: Rennoll-Bankert KE, Rahman MS, Gillespie JJ, Guillotte ML, Kaur SJ, Lehman SS, Beier-Sexton M, Azad AF
- Issue date: 2015 Aug
- The Cat Flea (Ctenocephalides felis) Immune Deficiency Signaling Pathway Regulates Rickettsia typhi Infection.
- Authors: Rennoll SA, Rennoll-Bankert KE, Guillotte ML, Lehman SS, Driscoll TP, Beier-Sexton M, Rahman MS, Gillespie JJ, Azad AF
- Issue date: 2018 Jan