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Importantly, diverse\n            <jats:named-content content-type=\"genus-species\">Rickettsia<\/jats:named-content>\n            species are predicted to utilize divergent mechanisms to colonize host cells, as nearly all adhesins and effectors involved in host cell entry are differentially encoded in diverse\n            <jats:named-content content-type=\"genus-species\">Rickettsia<\/jats:named-content>\n            species. One particular effector, RalF, a Sec7 domain-containing protein that functions as a guanine nucleotide exchange factor of ADP-ribosylation factors (Arfs), is critical for\n            <jats:named-content content-type=\"genus-species\">Rickettsia typhi<\/jats:named-content>\n            (typhus group rickettsiae) entry but pseudogenized or absent from spotted fever group rickettsiae. Secreted early during\n            <jats:named-content content-type=\"genus-species\">R. typhi<\/jats:named-content>\n            infection, RalF localizes to the host plasma membrane and interacts with host ADP-ribosylation factor 6 (Arf6). Herein, we demonstrate that RalF activates Arf6, a process reliant on a conserved Glu within the RalF Sec7 domain. Furthermore, Arf6 is activated early during infection, with GTP-bound Arf6 localized to the\n            <jats:named-content content-type=\"genus-species\">R. typhi<\/jats:named-content>\n            entry foci. The regulation of phosphatidylinositol 4-phosphate 5-kinase (PIP5K), which generates PI(4,5)P\n            <jats:sub>2<\/jats:sub>\n            , by activated Arf6 is instrumental for bacterial entry, corresponding to the requirement of PI(4,5)P\n            <jats:sub>2<\/jats:sub>\n            for\n            <jats:named-content content-type=\"genus-species\">R. typhi<\/jats:named-content>\n            entry. PI(3,4,5)P\n            <jats:sub>3<\/jats:sub>\n            is then synthesized at the entry foci, followed by the accumulation of PI(3)P on the short-lived vacuole. Inhibition of phosphoinositide 3-kinases, responsible for the synthesis of PI(3,4,5)P\n            <jats:sub>3<\/jats:sub>\n            and PI(3)P, negatively affects\n            <jats:named-content content-type=\"genus-species\">R. typhi<\/jats:named-content>\n            infection. Collectively, these results identify RalF as the first bacterial effector to directly activate Arf6, a process that initiates alterations in phosphoinositol metabolism critical for a lineage-specific\n            <jats:named-content content-type=\"genus-species\">Rickettsia<\/jats:named-content>\n            entry mechanism.\n          <\/jats:p>","DOI":"10.1128\/iai.00638-16","type":"journal-article","created":{"date-parts":[[2016,10,4]],"date-time":"2016-10-04T02:39:14Z","timestamp":1475548754000},"page":"3496-3506","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":32,"title":["RalF-Mediated Activation of Arf6 Controls Rickettsia typhi Invasion by Co-Opting Phosphoinositol Metabolism"],"prefix":"10.1128","volume":"84","author":[{"given":"Kristen E.","family":"Rennoll-Bankert","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. Sayeedur","family":"Rahman","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark L.","family":"Guillotte","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie S.","family":"Lehman","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magda","family":"Beier-Sexton","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph J.","family":"Gillespie","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdu F.","family":"Azad","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.micro.61.080706.093305"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1090124"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mib.2013.11.005"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0966-842X(00)88982-9"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2112"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-6976.2011.00271.x"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2007.06.005"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro3009"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-cellbio-100913-013439"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1111\/cmi.12334"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2014.09.005"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00002.2012"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.4161\/sgtp.29469"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.150.6.1299"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.150.6.1311"},{"key":"e_1_3_2_17_2","first-page":"8741","article-title":"Type I phosphatidylinositol-4-phosphate 5-kinases","volume":"273","author":"Ishihara H","year":"1998","unstructured":"Ishihara H, Shibasaki Y, Kizuki N, Wada T, Yazaki Y, Asano T, Oka Y. 1998. 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