HIF-1α is involved in mediating apoptosis resistance to Chlamydia trachomatis-infected cells.

Authors:
Manu Sharma, Nikolaus Machuy, Linda Böhme, Karthika Karunakaran, André P Mäurer, Thomas F Meyer, Thomas Rudel
Year of publication:
2011
Volume:
13
Issue:
10
Issn:
1462-5814
Journal title abbreviated:
Cell. Microbiol.
Journal title long:
Cellular microbiology
Impact factor:
4.816
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.