title: HIF-1α is involved in mediating apoptosis resistance to Chlamydia trachomatis-infected cells.
abstract: Chlamydiae are obligate intracellular Gram-negative bacteria that cause widespread diseases in humans. Due to the intimate association between bacterium and host, Chlamydia evolved various strategies to protect their host cell against death-inducing stimuli, allowing the bacterium to complete its development cycle. An RNA interference (RNAi)-based screen was used to identify host cell factors required for apoptosis resistance of human epithelial cells infected with Chlamydia trachomatis serovar L2. Among the 32 validated hits, the anti-apoptotic Bcl-2 family member Mcl-1 was identified as a target. Protein network analyses implicated the transcription factor hypoxia-induced factor 1 alpha (HIF-1α) to be central to the regulation of many of the identified targets. Further mechanistic investigations showed that HIF-1α was stabilized within the host cell cytoplasm during early infection time points, followed by its translocation to the nucleus and eventual transcriptional activation of Mcl-1. siRNA-mediated depletion of HIF-1α led to a drastic decrease in Mcl-1, rendering the cell sensitive to apoptosis induction. Taken together, our findings identify HIF-1α as responsible for upregulation of Mcl-1 and the maintenance of apoptosis resistance during Chlamydia infection.
authors.affiliation: Max Planck Institute for Infection Biology, Department of Molecular Biology, Charitéplatz 1, D-10117 Berlin, Germany.
authors.forename: Manu
authors.initials: M
authors.lastname: Sharma
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Machuy
authors.forename: Linda
authors.initials: L
authors.lastname: Böhme
authors.forename: Karthika
authors.initials: K
authors.lastname: Karunakaran
authors.forename: André P
authors.initials: AP
authors.lastname: Mäurer
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Meyer
authors.forename: Thomas
authors.initials: T
authors.lastname: Rudel
mesh_terms: D017209:Apoptosis; D002460:Cell Line; D002692:Chlamydia trachomatis / Q000472:pathogenicity*; D004847:Epithelial Cells / Q000382:microbiology; D055785:Gene Knockdown Techniques; D005820:Genetic Testing; D054884:Host-Pathogen Interactions; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D034622:RNA Interference; D049490:Systems Biology / Q000379:methods
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2