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Türköz, Gözde
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Meier, K., Jachmann, L. H., Türköz, G., Babu Sait, M. R., Pérez, L., Kepp, O., . . . Sixt, B. S. (2023). The Chlamydia effector CpoS modulates the inclusion microenvironment and restricts the interferon response by acting on Rab35. mBio, 14(4), Article ID e0319022.
Open this publication in new window or tab >>The Chlamydia effector CpoS modulates the inclusion microenvironment and restricts the interferon response by acting on Rab35
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2023 (English)In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 14, no 4, article id e0319022Article in journal (Refereed) Published
Abstract [en]

The obligate intracellular bacterium Chlamydia trachomatis inserts a family of inclusion membrane (Inc) proteins into the membrane of its vacuole (the inclusion). The Inc CpoS is a critical suppressor of host cellular immune surveillance, but the underlying mechanism remained elusive. By complementing a cpoS mutant with various natural orthologs and variants of CpoS, we linked distinct molecular interactions of CpoS to distinct functions. Unexpectedly, we found CpoS to be essential for the formation of inclusion membrane microdomains that control the spatial organization of multiple Incs involved in signaling and modulation of the host cellular cytoskeleton. While the function of CpoS in microdomains was uncoupled from its role in the suppression of host cellular defenses, we found the ability of CpoS to interact with Rab GTPases to be required not only for the manipulation of membrane trafficking, such as to mediate transport of ceramide-derived lipids (sphingolipids) to the inclusion, but also for the inhibition of Stimulator of interferon genes (STING)-dependent type I interferon responses. Indeed, depletion of Rab35 phenocopied the exacerbated interferon responses observed during infection with CpoS-deficient mutants. Overall, our findings highlight the role of Inc-Inc interactions in shaping the inclusion microenvironment and the modulation of membrane trafficking as a pathogenic immune evasion strategy.

IMPORTANCE: Chlamydia trachomatis is a prevalent bacterial pathogen that causes blinding ocular scarring and urogenital infections that can lead to infertility and pregnancy complications. Because Chlamydia can only grow within its host cell, boosting the intrinsic defenses of human cells may represent a novel strategy to fight pathogen replication and survival. Hence, CpoS, a Chlamydia protein known to block host cellular defenses, or processes regulated by CpoS, could provide new opportunities for therapeutic intervention. By revealing CpoS as a multifunctional virulence factor and by linking its ability to block host cellular immune signaling to the modulation of membrane trafficking, the present work may provide a foundation for such rationale targeting and advances our understanding of how intracellular bacteria can shape and protect their growth niche.

Place, publisher, year, edition, pages
American Society for Microbiology, 2023
Keywords
cell-autonomous immunity, interferon responses, intracellular bacteria, membrane microdomains, membrane trafficking, Rab GTPases
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-214251 (URN)10.1128/mbio.03190-22 (DOI)001041120000001 ()37530528 (PubMedID)2-s2.0-85169501656 (Scopus ID)
Funder
European Commission, PIOF-GA-2013-626116Swedish Research Council, 2016-06598Swedish Research Council, 2018-02286Swedish Research Council, 2021-06602Swedish Research Council, 2022-00852NIH (National Institutes of Health), AI100759; AI134891
Available from: 2023-09-18 Created: 2023-09-18 Last updated: 2023-09-18Bibliographically approved
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