Targeting of a Chlamydial Protease Impedes Intracellular Bacterial Growth

Autor: Georg Häcker, Jan Rupp, Stefan A. Paschen, Thomas F. Meyer, Juliane Vier, Dagmar Heuer, Jan G. Christian, Linda Schauenburg, Julia Heymann
Rok vydání: 2011
Předmět:
medicine.medical_treatment
Vesicular Transport Proteins
Golgi Apparatus
Chlamydia trachomatis
Vacuole
medicine.disease_cause
Biochemistry
Molecular Cell Biology
RNA
Small Interfering
lcsh:QH301-705.5
Cell Death
biology
Microbial Growth and Development
Chlamydophila pneumoniae
Cellular Structures
Bacterial Biochemistry
Cell biology
Host-Pathogen Interaction
Medical Microbiology
symbols
RNA Interference
Oligopeptides
Intracellular
Research Article
lcsh:Immunologic diseases. Allergy
Immunology
Chlamydiae
Cleavage (embryo)
Microbiology
Cell Line
symbols.namesake
Virology
Endopeptidases
Genetics
medicine
Humans
Biology
Microbial Pathogens
Molecular Biology
Protease
Cell-Free System
Intracellular parasite
Golgi Matrix Proteins
Membrane Proteins
Proteins
Bacteriology
Golgi apparatus
biology.organism_classification
HEK293 Cells
lcsh:Biology (General)
Subcellular Organelles
rab GTP-Binding Proteins
Parasitology
lcsh:RC581-607
HeLa Cells
Zdroj: PLoS Pathogens
PLoS Pathogens, Vol 7, Iss 9, p e1002283 (2011)
ISSN: 1553-7374
DOI: 10.1371/journal.ppat.1002283
Popis: Chlamydiae are obligate intracellular bacteria that propagate in a cytosolic vacuole. Recent work has shown that growth of Chlamydia induces the fragmentation of the Golgi apparatus (GA) into ministacks, which facilitates the acquisition of host lipids into the growing inclusion. GA fragmentation results from infection-associated cleavage of the integral GA protein, golgin-84. Golgin-84-cleavage, GA fragmentation and growth of Chlamydia trachomatis can be blocked by the peptide inhibitor WEHD-fmk. Here we identify the bacterial protease chlamydial protease-like activity factor (CPAF) as the factor mediating cleavage of golgin-84 and as the target of WEHD-fmk-inhibition. WEHD-fmk blocked cleavage of golgin-84 as well as cleavage of known CPAF targets during infection with C. trachomatis and C. pneumoniae. The same effect was seen when active CPAF was expressed in non-infected cells and in a cell-free system. Ectopic expression of active CPAF in non-infected cells was sufficient for GA fragmentation. GA fragmentation required the small GTPases Rab6 and Rab11 downstream of CPAF-activity. These results define CPAF as the first protein that is essential for replication of Chlamydia. We suggest that this role makes CPAF a potential anti-infective therapeutic target.
Author Summary Chlamydiae are bacteria that replicate only inside host (for instance human) cells and that are frequent agents of human disease, in particular sexually transmitted disease. Chlamydia lives in a vacuole inside the cell, surrounded by a lipid membrane, and must acquire nutrients and other factors from the host cell for its replication and for the growth of the vacuole. Recent results show that for this, Chlamydia relies on its ability to induce the loss of an individual protein of the Golgi apparatus (a cellular structure that sorts materials for transport in the cell) called golgin-84. In this work we find that Chlamydia does this using its protein-cleaving enzyme CPAF (which is made by Chlamydia and transported from the vacuole into the cell). CPAF cleaves golgin-84 and thereby induces changes in the Golgi apparatus that are linked to the acquisition of some cellular material by Chlamydia. We further show that a synthetic inhibitor, which was recently found to block chlamydial growth, does that by inhibiting CPAF. CPAF therefore seems necessary for chlamydial growth and blocking CPAF may be a therapeutic strategy against infections with Chlamydia.
Databáze: OpenAIRE
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