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Cleavage of host keratin 8 by a Chlamydia-secreted protease.

ABSTRACT: Chlamydiae have to replicate within a cytoplasmic vacuole in eukaryotic cells. Expansion of the chlamydia-laden vacuole is essential for chlamydial intravacuolar replication, which inevitably causes host cell cytoskeleton rearrangements. A cleavage fragment of keratin 8 corresponding to the central rod region was detected in the soluble fraction of chlamydia-infected cells. Since keratin 8 is a major component of the intermediate filaments in simple epithelial cells, cleavage of keratin 8 may increase the solubility of the host cell cytoskeleton and thus permit vacuole expansion in chlamydia-infected cells. A chlamydia-secreted protease designated CPAF (chlamydial protease/proteasome-like activity factor) was both necessary and sufficient for keratin 8 cleavage in chlamydia-infected cells, suggesting that chlamydiae have evolved specific mechanisms for modifying the host cell cytoskeleton.

SUBMITTER: Dong F

PROVIDER: S-EPMC427399 | biostudies-literature | 2004 Jul

REPOSITORIES: biostudies-literature

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Cleavage of host keratin 8 by a Chlamydia-secreted protease.

Dong Feng F Su Heng H Huang Yanqing Y Zhong Youmin Y Zhong Guangming G

Infection and immunity 20040701 7

Chlamydiae have to replicate within a cytoplasmic vacuole in eukaryotic cells. Expansion of the chlamydia-laden vacuole is essential for chlamydial intravacuolar replication, which inevitably causes host cell cytoskeleton rearrangements. A cleavage fragment of keratin 8 corresponding to the central rod region was detected in the soluble fraction of chlamydia-infected cells. Since keratin 8 is a major component of the intermediate filaments in simple epithelial cells, cleavage of keratin 8 may in ...[more]

PMID: 15213128

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Project description:The secreted Chlamydia protease CPAF cleaves a defined set of mammalian and Chlamydia proteins in vitro. As a result, this protease has been proposed to modulate a range of bacterial and host cellular functions. However, it has recently come into question the extent to which many of its identified substrates constitute bona fide targets of proteolysis in infected host cell rather than artifacts of postlysis degradation. Here, we clarify the role played by CPAF in cellular models of infection by analyzing Chlamydia trachomatis mutants deficient for CPAF activity. Using reverse genetic approaches, we identified two C. trachomatis strains possessing nonsense, loss-of-function mutations in cpa (CT858) and a third strain containing a mutation in type II secretion (T2S) machinery that inhibited CPAF activity by blocking zymogen secretion and subsequent proteolytic maturation into the active hydrolase. HeLa cells infected with T2S(-) or CPAF(-) C. trachomatis mutants lacked detectable in vitro CPAF proteolytic activity and were not defective for cellular traits that have been previously attributed to CPAF activity, including resistance to staurosporine-induced apoptosis, Golgi fragmentation, altered NFκB-dependent gene expression, and resistance to reinfection. However, CPAF-deficient mutants did display impaired generation of infectious elementary bodies (EBs), indicating an important role for this protease in the full replicative potential of C. trachomatis. In addition, we provide compelling evidence in live cells that CPAF-mediated protein processing of at least two host protein targets, vimentin filaments and the nuclear envelope protein lamin-associated protein-1 (LAP1), occurs rapidly after the loss of the inclusion membrane integrity, but before loss of plasma membrane permeability and cell lysis. CPAF-dependent processing of host proteins correlates with a loss of inclusion membrane integrity, and so we propose that CPAF plays a role late in infection, possibly during the stages leading to the dismantling of the infected cell prior to the release of EBs during cell lysis.

Dataset Information

Cleavage of host keratin 8 by a Chlamydia-secreted protease.

Publications

Cleavage of host keratin 8 by a Chlamydia-secreted protease.

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