The Secreted Protease Factor CPAF Is Responsible for Degrading Pro-apoptotic BH3-only Proteins in<i>Chlamydia trachomatis</i>-infected Cells

Pirbhai, Mustak; Dong, Feng; Zhong, Youmin; Pan, Kelvin Z.; Zhong, Guangming

doi:10.1074/jbc.m602796200

Cited by 111 publications

(107 citation statements)

References 43 publications

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“…5B). CT858 also encodes CPAF, a tail-specific protease (Tsp) of Chlamydia sp., which has previously been reported to promote protein degradation of RFX5 transcriptional factor (24) and Bim protein of apoptosis (25). In addition to lack of p65 cleavage activity, it is worth noting that CPAF also differs from CT441 in that CPAF activity was not detected from purified Chlamydia (26), whereas p65 cleavage activity was found from purified bacteria as well as during an infection.…”

Section: To Investigate Whethermentioning

confidence: 86%

Cleavage of p65/RelA of the NF-κB pathway by Chlamydia

Lad

Correia

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

107

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Chlamydia trachomatis is a bacterial pathogen that infects the eyes and urogenital tract. Ocular infection by this organism is the leading cause of preventable blindness worldwide. The infection is also a leading cause of sexually transmitted disease in the United States. As obligate intracellular pathogens, chlamydiae have evolved sophisticated, yet undefined, mechanisms to maintain a favorable habitat for intracellular growth while avoiding harm to the host. We show here that chlamydiae have the ability to interfere with the NF-B pathway of host inflammatory response. We found that Chlamydia infection did not promote I B␣ degradation, a prerequisite for NF-B nuclear translocation/activation, nor induce p65/RelA nuclear redistribution. Instead, it caused p65 cleavage into an N terminus-derived p40 fragment and a p22 of the C terminus. The activity was specific because no protein cleavage or degradation of NF-B pathway components was detected. Moreover, murine p65 protein was resistant to cleavage by both human and mouse biovars. The chlamydial protein that selectively cleaved p65 was identified as a tail-specific protease (CT441). Importantly, expression of either this protease or the p40 cleavage product could block NF-B activation. A hallmark of chlamydial STD is its asymptomatic nature, although inflammatory cellular response and chronic inflammation are among the underlying mechanisms. The data presented here demonstrate that chlamydiae have the ability to convert a regulatory molecule of host inflammatory response to a dominant negative inhibitor of the same pathway potentially to minimize inflammation.CT441 ͉ inflammation ͉ protease

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Section: To Investigate Whethermentioning

confidence: 86%

Cleavage of p65/RelA of the NF-κB pathway by Chlamydia

Lad

Correia

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

107

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“…In the microbial world, a number of bacterial toxins have been reported to manipulate the host cell apoptosis, either inducing or protecting from this type of cell death Pirbhai et al, 2006). CNF1-producing E. coli can benefit from prolonged host cell survival because they obtain a protected niche wherein they survive (Rajalingam et al, 2001), and they form a persistent reservoir that can account for recurrent infections.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic Necrotizing Factor 1 Prevents Apoptosis via the Akt/IκB Kinase Pathway: Role of Nuclear Factor-κB and Bcl-2

Miraglia

Travaglione²,

Meschini

et al. 2007

MBoC

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Cytotoxic necrotizing factor 1 (CNF1) is a protein toxin produced by some pathogenic strains of Escherichia coli that specifically activates Rho, Rac, and Cdc42 GTPases. We previously reported that this toxin prevents the ultraviolet-Binduced apoptosis in epithelial cells, with a mechanism that remained to be defined. In this work, we show that the proteasomal degradation of the Rho GTPase is necessary to achieve cell death protection, because inhibition of Rho degradation abolishes the prosurvival activity of CNF1. We hypothesize that Rho inactivation allows the activity of Rac to become dominant. This in turn leads to stimulation of the phosphoinositide 3-kinase/Akt/I B kinase/nuclear factor-B prosurvival pathway and to a remarkable modification in the architecture of the mitochondrial network, mainly consisting in the appearance of elongated and interconnected mitochondria. Importantly, we found that Bcl-2 silencing reduces the ability of CNF1 to protect cells against apoptosis and that it also prevents the CNF1-induced mitochondrial changes. It is worth noting that the ability of a bacterial toxin to induce such a remodeling of the mitochondrial network is herein reported for the first time. The possible pathophysiological relevance of this finding is discussed. INTRODUCTIONToday, it is largely acknowledged that apoptosis, besides being an evolutionary conserved form of cell death that plays a pivotal role during development, morphogenesis, and cell homeostasis, is also critically implied in a constantly growing number of diseases (Fadeel and Orrenius, 2005). In fact, apoptosis can be regarded as a widespread strategy exploited by pathogenic bacteria to favor their own survival or spreading in the host , often by producing protein toxins that mediate their long-range cross-talk with host cells. In this context, we have previously reported the ability of a protein toxin from Escherichia coli, namely the cytotoxic necrotizing factor 1 (CNF1), to prevent the ultraviolet-B (UVB)-induced apoptosis and to increase the expression of antiapoptotic Bcl-2 family proteins (Fiorentini et al., 1998). The precise mechanism by which CNF1 allows cells to survive, however, is not yet defined.CNF1 is a protein toxin produced by some pathogenic strains of E. coli mainly involved in extraintestinal infections (Landraud et al., 2000). In eukaryotic cells, CNF1 binds to its receptor, reported to be the receptor of laminin , and it is endocytosed and released into the cytoplasm by an acidic-dependent mechanism (Contamin et al., 2000). Once in the cytoplasm, CNF1 exerts its enzymatic activity that is represented by deamidation of a pivotal glutamine residue of the guanosine triphosphate (GTP)-binding proteins Rho, Rac, and Cdc42 (glutamine 63 of Rho or glutamine 61 of Rac and Cdc42), giving rise to a glutamic acid (Flatau et al., 1997;Schmidt et al., 1997;Lerm et al., 1999). The glutamine residue modified by CNF1 lies in the switch 2 domain of Rho proteins, which is involved in GTP hydrolysis; thus, the modification exerted by CNF1...

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“…In addition to downregulating MHC expression, CPAF has more recently been demonstrated to also degrade pro-apoptotic BH3-only proteins (Pirbhai et al, 2006). The ability of Chlamydia to degrade BH3-only proteins, as well as sequester pro-apoptotic proteins and induce the expression of antiapoptotic factors, may explain the longstanding observation that Chlamydia-infected cells are largely resistant to immune-mediated induction of apoptosis in vitro (Byrne and Ojcius, 2004;Miyairi and Byrne, 2006).…”

Section: Immune Evasion By C Trachomatismentioning

confidence: 99%

Immune-mediated control of Chlamydia infection

Roan

Starnbach²

2007

Cell Microbiol

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SummaryInfection with the bacterium Chlamydia trachomatis can lead to a variety of diseases, including ectopic pregnancy, infertility and blindness. Exposure of the host to C. trachomatis stimulates multiple innate and adaptive immune effectors that can contribute towards controlling bacterial replication. However, these effectors are often insufficient to resolve the infection and prevent re-infection, and the continued presence of C. trachomatis within the host may induce immune effectors to chronically produce inflammatory cytokines. This may eventually lead to the tissue pathologies associated with the infection. Reducing the incidence and sequelae of infection will ultimately require the development of a C. trachomatis vaccine that can stimulate sterilizing immunity while avoiding immune-mediated pathology.

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The Secreted Protease Factor CPAF Is Responsible for Degrading Pro-apoptotic BH3-only Proteins inChlamydia trachomatis-infected Cells

Cited by 111 publications

References 43 publications

Cleavage of p65/RelA of the NF-κB pathway by Chlamydia

Cleavage of p65/RelA of the NF-κB pathway by Chlamydia

Cytotoxic Necrotizing Factor 1 Prevents Apoptosis via the Akt/IκB Kinase Pathway: Role of Nuclear Factor-κB and Bcl-2

Immune-mediated control of Chlamydia infection

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