title: Legionella suppresses the host unfolded protein response via multiple mechanisms.
abstract: The intracellular pathogen, Legionella pneumophila, secretes ∼300 effector proteins to modulate the host environment. Given the intimate interaction between L. pneumophila and the endoplasmic reticulum, we investigated the role of the host unfolded protein response (UPR) during L. pneumophila infection. Interestingly, we show that the host identifies L. pneumophila infection as a form of endoplasmic reticulum stress and the sensor pATF6 is processed to generate pATF6(N), a transcriptional activator of downstream UPR genes. However, L. pneumophila is able to suppress the UPR and block the translation of prototypical UPR genes, BiP and CHOP. Furthermore, biochemical studies reveal that L. pneumophila uses two effectors (Lgt1 and Lgt2) to inhibit the splicing of XBP1u mRNA to spliced XBP1 (XBP1s), an UPR response regulator. Thus, we demonstrate that L. pneumophila is able to inhibit the UPR by multiple mechanisms including blocking XBP1u splicing and causing translational repression. This observation highlights the utility of L. pneumophila as a powerful tool for studying a critical protein homeostasis regulator.
authors.affiliation: 1] Department of Microbiology and Immunology, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, California 94143-0552, USA [2] Department of Microbiology and Immunology, George Williams Hooper Foundation, 513 Parnassus Avenue, Box 0552, Rm HSW 1522, San Francisco, California 94143-0552, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Treacy-Abarca
authors.affiliation: 1] Department of Microbiology and Immunology, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, California 94143-0552, USA [2] Department of Microbiology and Immunology, George Williams Hooper Foundation, 513 Parnassus Avenue, Box 0552, Rm HSW 1522, San Francisco, California 94143-0552, USA.
authors.forename: Shaeri
authors.initials: S
authors.lastname: Mukherjee
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism*; D015153:Blotting, Western; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D016952:Legionella pneumophila; D007877:Legionnaires' Disease / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism*; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism*; D000071701:Regulatory Factor X Transcription Factors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051742:Transcription Factor CHOP / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D056811:Unfolded Protein Response / Q000235:genetics*; D000071717:X-Box Binding Protein 1
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D001426:Bacterial Proteins; C497249:DDIT3 protein, human; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D051742:Transcription Factor CHOP