ArticlePLoS pathogens2015
Which Way In? The RalF Arf-GEF Orchestrates Rickettsia Host Cell Invasion.
Article in PLoS pathogens, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers, 1 of them a synthesis that pooled it.
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Who cites it
37 citing papers in PubMed, 1 synthesis or guideline pooled it, 54 citations in OpenAlex.
- Genomic evolution and adaptation of arthropod-associated Rickettsia.Scientific reports · 2022Pooled it
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- Phosphatidylserine-binding receptor, CD300f, on macrophages mediates host invasion of pathogenic and non-pathogenic rickettsiae.Infection and immunity · 2025Article
- Genomic characteristics of emerging human pathogeniScience · 2025Article
- Pathogenic rickettsiae encode a secreted lipase that facilitates intracytosolic colonization in host cells.PloS one · 2025Article
- A conserved interaction between the effector Sca4 and host clathrin suggests additional contributions for Sca4 during rickettsial infection.Infection and immunity · 2024Article
- Article
- Cell-selective proteomics reveal novel effectors secreted by an obligate intracellular bacterial pathogen.Nature communications · 2024Article
- Article
- Cat Flea Coinfection withVector borne and zoonotic diseases (Larchmont, N.Y.) · 2024Article
- PathogenicJournal of bacteriology · 2024Review
- Critical roles ofInfection and immunity · 2024Article
- Cell-selective proteomics reveal novel effectors secreted by an obligate intracellular bacterial pathogen.bioRxiv : the preprint server for biology · 2023Article
- Murine Typhus: A Review of a Reemerging Flea-Borne Rickettsiosis with Potential for Neurologic Manifestations and Sequalae.Infectious disease reports · 2023Review
- Targeting small GTPases: emerging grasps on previously untamable targets, pioneered by KRAS.Signal transduction and targeted therapy · 2023Review
- Metagenome diversity illuminates origins of pathogen effectors.bioRxiv : the preprint server for biology · 2023Article
- Analysis of the Type 4 Effectome across the GenusInternational journal of molecular sciences · 2022Article
- Pathogenicity and virulence ofVirulence · 2022Review
- Transposon mutagenesis of Rickettsia felis sca1 confers a distinct phenotype during flea infection.PLoS pathogens · 2022Article
- The Ankyrin Repeat Protein RARP-1 Is a Periplasmic Factor That SupportsJournal of bacteriology · 2022Article
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
Bacterial Sec7-domain-containing proteins (RalF) are known only from species of Legionella and Rickettsia, which have facultative and obligate intracellular lifestyles, respectively. L. pneumophila RalF, a type IV secretion system (T4SS) effector, is a guanine nucleotide exchange factor (GEF) of ADP-ribosylation factors (Arfs), activating and recruiting host Arf1 to the Legionella-containing vacuole. In contrast, previous in vitro studies showed R. prowazekii (Typhus Group) RalF is a functional Arf-GEF that localizes to the host plasma membrane and interacts with the actin cytoskeleton via a unique C-terminal domain. As RalF is differentially encoded across Rickettsia species (e.g., pseudogenized in all Spotted Fever Group species), it may function in lineage-specific biology and pathogenicity. Herein, we demonstrate RalF of R. typhi (Typhus Group) interacts with the Rickettsia T4SS coupling protein (RvhD4) via its proximal C-terminal sequence. RalF is expressed early during infection, with its inactivation via antibody blocking significantly reducing R. typhi host cell invasion. For R. typhi and R. felis (Transitional Group), RalF ectopic expression revealed subcellular localization with the host plasma membrane and actin cytoskeleton. Remarkably, R. bellii (Ancestral Group) RalF showed perinuclear localization reminiscent of ectopically expressed Legionella RalF, for which it shares several structural features. For R. typhi, RalF co-localization with Arf6 and PI(4,5)P2 at entry foci on the host plasma membrane was determined to be critical for invasion. Thus, we propose recruitment of PI(4,5)P2 at entry foci, mediated by RalF activation of Arf6, initiates actin remodeling and ultimately facilitates bacterial invasion. Collectively, our characterization of RalF as an invasin suggests that, despite carrying a similar Arf-GEF unknown from other bacteria, different intracellular lifestyles across Rickettsia and Legionella species have driven divergent roles for RalF during infection. Furthermore, our identification of lineage-specific Arf-GEF utilization across some rickettsial species illustrates different pathogenicity factors that define diverse agents of rickettsial diseases.
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