The Chlamydia trachomatis Inclusion Membrane Protein CpoS Counteracts STING-Mediated Cellular Surveillance and Suicide Programs

Sixt, Barbara S.; Bastidas, Robert J.; Finethy, Ryan; Baxter, Ryan M.; Carpenter, Victoria K.; Kroemer, Guido; Coers, Jörn; Valdivia, Raphael H.

doi:10.1016/j.chom.2016.12.002

Cited by 110 publications

(175 citation statements)

References 45 publications

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“…During infection in mammals, bacteria such as Chlamydia generate CDNs that activate the innate immune response in a STING-dependent and cGAS-independent manner (Sixt et al, 2017; Webster et al, 2017). Listeria secretes c-di-AMPs to induce an IFN response that stimulates the STING pathway (Sauer et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Analysis of Drosophila STING Reveals an Evolutionarily Conserved Antimicrobial Function

et al. 2018

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SUMMARY The vertebrate protein STING, an intracellular sensor of cyclic dinucleotides, is critical to the innate immune response and the induction of type I interferon during pathogenic infection. Here, we show that a STING ortholog (dmSTING) exists in Drosophila, which, similar to vertebrate STING, associates with cyclic dinucleotides to initiate an innate immune response. Following infection with Listeria monocytogenes, dmSTING activates an innate immune response via activation of the NF-κB transcription factor Relish, part of the immune deficiency (IMD) pathway. DmSTING-mediated activation of the immune response reduces the levels of Listeria-induced lethality and bacterial load in the host. Of significance, dmSTING triggers an innate immune response in the absence of a known functional cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) ortholog in the fly. Together, our results demonstrate that STING is an evolutionarily conserved antimicrobial effector between flies and mammals, and it comprises a key component of host defense against pathogenic infection in Drosophila.

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Section: Discussionmentioning

confidence: 99%

Analysis of Drosophila STING Reveals an Evolutionarily Conserved Antimicrobial Function

et al. 2018

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“…Of 11 Inc mutants examined here, 3 Incs were identified that play a role in mediating vacuolar integrity. A recent study demonstrated that disruption of CT229 (CpoS) leads to host cell death and activiation of the STING pathway (Sixt et al, 2017). The authors propose that this represents a direct effect of CT229 suppressing IFN responses by interfering with membrane-trafficking events to block STING translocation.…”

Section: Discussionmentioning

confidence: 99%

Absence of Specific Chlamydia trachomatis Inclusion Membrane Proteins Triggers Premature Inclusion Membrane Lysis and Host Cell Death

et al. 2017

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Summary Chlamydia trachomatis is a human pathogen associated with significant morbidity worldwide. As obligate intracellular parasites, chlamydiae must survive within eukaryotic cells for sufficient time to complete their developmental cycle. To promote host cell survival, chlamydiae express poorly understood anti-apoptotic factors. Using recently developed genetic tools, we show that three inclusion membrane proteins (Incs) out of eleven examined are required for inclusion membrane stability and avoidance of host cell death pathways. In the absence of specific Incs, premature inclusion lysis results in recognition by autophagolysosomes, activation of intrinsic apoptosis, and premature termination of the chlamydial developmental cycle. Inhibition of autophagy or knockdown of STING prevented host cell death and activation of intrinsic apoptosis. Significantly these findings emphasize the importance of Incs in the establishment of a replicative compartment that sequesters the pathogen from host surveillance systems.

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“…However, it is unknown if Inc proteins can also act as structural components to bring and maintain the ER and the inclusion membrane in close apposition. C. trachomatis encodes more than 50 putative Incs and only some of them have known functions in C. trachomatis infection (24,28,(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43). Recently, Mirrashidi et al (37) determined the Inc-human interactome from uninfected cells expressing C. trachomatis Inc proteins.…”

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confidence: 99%

IncV, a FFAT motif-containing Chlamydia protein, tethers the endoplasmic reticulum to the pathogen-containing vacuole

Stanhope

Flora

Bayne

et al. 2017

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

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Membrane contact sites (MCS) are zones of contact between the membranes of two organelles. At MCS, specific proteins tether the organelles in close proximity and mediate the nonvesicular trafficking of lipids and ions between the two organelles. The endoplasmic reticulum (ER) integral membrane protein VAP is a common component of MCS involved in both tethering and lipid transfer by binding directly to proteins containing a FFAT [two phenylalanines (FF) in an acidic tract (AT)] motif. In addition to maintaining cell homeostasis, MCS formation recently emerged as a mechanism by which intracellular pathogens hijack cellular resources and establish their replication niche. Here, we investigated the mechanism by which the Chlamydia-containing vacuole, termed the inclusion, establishes direct contact with the ER. We show that the Chlamydia protein IncV, which is inserted into the inclusion membrane, displays one canonical and one noncanonical FFAT motif that cooperatively mediated the interaction of IncV with VAP. IncV overexpression was sufficient to bring the ER in close proximity of IncV-containing membranes. Although IncV deletion partially decreased VAP association with the inclusion, it did not suppress the formation of ER-inclusion MCS, suggesting the existence of redundant mechanisms in MCS formation. We propose a model in which IncV acts as one of the primary tethers that contribute to the formation of ER-inclusion MCS. Our results highlight a previously unidentified mechanism of bacterial pathogenesis and support the notion that cooperation of two FFAT motifs may be a common feature of VAP-mediated MCS formation. Chlamydiahost cell interaction therefore constitutes a unique system to decipher the molecular mechanisms underlying MCS formation.endoplasmic reticulum-Chlamydia inclusion membrane contact sites | IncV | FFAT motif | VAP proteins | tether

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The Chlamydia trachomatis Inclusion Membrane Protein CpoS Counteracts STING-Mediated Cellular Surveillance and Suicide Programs

Cited by 110 publications

References 45 publications

Analysis of Drosophila STING Reveals an Evolutionarily Conserved Antimicrobial Function

Analysis of Drosophila STING Reveals an Evolutionarily Conserved Antimicrobial Function

Absence of Specific Chlamydia trachomatis Inclusion Membrane Proteins Triggers Premature Inclusion Membrane Lysis and Host Cell Death

IncV, a FFAT motif-containing Chlamydia protein, tethers the endoplasmic reticulum to the pathogen-containing vacuole

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