title: The Roles of Unfolded Protein Response Pathways in Chlamydia Pathogenesis.
abstract: Chlamydia is an obligate intracellular bacterium that relies on host cells for essential nutrients and adenosine triphosphate (ATP) for a productive infection. Although the unfolded protein response (UPR) plays a major role in certain microbial infectivity, its role in chlamydial pathogenesis is unknown. We hypothesized that Chlamydia induces UPR and exploits it to upregulate host cell uptake and metabolism of glucose, production of ATP, phospholipids, and other molecules required for its replicative development and host survival. Using a combination of biochemical and pathway inhibition assays, we showed that the 3 UPR pathway transducers-protein kinase RNA-activated (PKR)-like ER kinase (PERK), inositol-requiring enzyme-1α (IRE1α), and activating transcription factor-6α (ATF6α)-were activated during Chlamydia infection. The kinase activity of PERK and ribonuclease (RNase) of IRE1α mediated the upregulation of hexokinase II and production of ATP via substrate-level phosphorylation. In addition, the activation of PERK and IRE1α promoted autophagy formation and apoptosis resistance for host survival. Moreover, the activation of IRE1α resulted in the generation of spliced X-box binding protein 1 (sXBP1) and upregulation of lipid production. The vital role of UPR pathways in Chlamydia development and pathogenesis could lead to the identification of potential molecular targets for therapeutics against Chlamydia.
authors.affiliation: Centers for Disease Control and Prevention, and.
authors.forename: Zenas
authors.initials: Z
authors.lastname: George
authors.affiliation: Centers for Disease Control and Prevention, and.|Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, Georgia.
authors.forename: Yusuf
authors.initials: Y
authors.lastname: Omosun
authors.affiliation: Department of Biomedical Sciences, University of Wisconsin, Milwaukee.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Azenabor
authors.affiliation: Centers for Disease Control and Prevention, and.
authors.forename: James
authors.initials: J
authors.lastname: Partin
authors.affiliation: Centers for Disease Control and Prevention, and.
authors.forename: Kahaliah
authors.initials: K
authors.lastname: Joseph
authors.affiliation: Centers for Disease Control and Prevention, and.
authors.forename: Debra
authors.initials: D
authors.lastname: Ellerson
authors.affiliation: Centers for Disease Control and Prevention, and.|Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, Georgia.
authors.forename: Qing
authors.initials: Q
authors.lastname: He
authors.affiliation: Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, Georgia.
authors.forename: Francis
authors.initials: F
authors.lastname: Eko
authors.affiliation: Centers for Disease Control and Prevention, and.
authors.forename: Claudiu
authors.initials: C
authors.lastname: Bandea
authors.affiliation: Centers for Disease Control and Prevention, and.
authors.forename: Pavel
authors.initials: P
authors.lastname: Svoboda
authors.affiliation: Centers for Disease Control and Prevention, and.
authors.forename: Jan
authors.initials: J
authors.lastname: Pohl
authors.affiliation: Centers for Disease Control and Prevention, and.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Black
authors.affiliation: Centers for Disease Control and Prevention, and.
authors.forename: Joseph U
authors.initials: JU
authors.lastname: Igietseme
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D002689:Chlamydia / Q000472:pathogenicity*; D002690:Chlamydia Infections / Q000378:metabolism / Q000382:microbiology*; D004722:Endoribonucleases / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D051702:Activating Transcription Factor 6; D004722:Endoribonucleases; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; C497112:Atf6 protein, mouse; C510185:Ern1 protein, mouse
keywords: Chlamydia; pathogenesis; unfolded protein response.