The bacterial effector GarD shields Chlamydia trachomatis inclusions from RNF213-mediated ubiquitylation and destruction

Walsh, Stephen; Reitano, Jeffrey R.; Dickinson, Mary S; Kutsch, Miriam; Hernandez, Dulcemaria; Barnes, Alyson B.; Schott, Benjamin H.; Wang, Liuyang; Ko, Dennis C.; Kim, So Young; Valdivia, Raphael H.; Bastidas, Robert J.; Coers, Jörn

doi:10.1016/j.chom.2022.08.008

Cited by 30 publications

(21 citation statements)

References 82 publications

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“…It was proposed that some inclusion membrane proteins play a structural role in maintaining inclusion membrane integrity ( 15 ). Moreover, a role in the specific inhibition of innate immune pathways and/or inclusion targeting by components of these pathways is supported by the fact that premature inclusion membrane rupture in the middle stages of the developmental cycle triggers host cell death pathways such as apoptosis, upon infection with C. trachomatis strains lacking CT229/CpoS, CT233/IncC, and CT383 ( 40 – 42 ). IncS Ct -negative inclusions were lysed earlier than wild-type inclusions; however, in comparison to strains lacking CT229/CpoS, CT233/IncC, or CT383, lysis occurred much later in the developmental cycle, suggesting that if IncS is also involved in counteracting innate immune defenses, it does so in the late development cycle.…”

Section: Discussionmentioning

confidence: 99%

Homologues of the Chlamydia trachomatis and Chlamydia muridarum Inclusion Membrane Protein IncS Are Interchangeable for Early Development but Not for Inclusion Stability in the Late Developmental Cycle

Cortina

Derré

2023

mSphere

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Section: Discussionmentioning

confidence: 99%

Homologues of the Chlamydia trachomatis and Chlamydia muridarum Inclusion Membrane Protein IncS Are Interchangeable for Early Development but Not for Inclusion Stability in the Late Developmental Cycle

Cortina

Derré

2023

mSphere

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“…A possible explanation for the lack of M1-speci c DUBs in other bacteria is the use of alternative mechanisms for avoiding decoration by linear chains. Recently, the effector protein GarD has been shown to shield C. trachomatis from linear chains -not by deubiquitination, but by altering the inclusion membrane to restrict access by ubiquitin ligases 11 . Homologs of GarD are present in other Chlamydiae but not in S. negevensis, compatible with the idea of GarD and SnOTU as alternative strategies of avoiding M1 ubiquitination.…”

Section: Discussionmentioning

confidence: 99%

“…Several intracellular bacteria have evolved effector proteins, which are secreted into the host cytoplasm and counteract ubiquitin-based defenses, e.g. by preventing ubiquitination [9][10][11] , removing ubiquitin chains 12,13 , or by interfering with ubiquitin-induced autophagy 14,15 .…”

Section: Introductionmentioning

confidence: 99%

Unexpected functional and structural diversity in deubiquitinases of the Chlamydia-like bacterium Simkania negevensis

Boll

Hermanns

Uthoff

et al. 2023

Preprint

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Besides the regulation of many cellular pathways, ubiquitination is important for the defence against invading pathogens. Some intracellular bacteria have evolved deubiquitinase (DUB) effector proteins, which interfere with the host ubiquitin system and help the pathogen to evade xenophagy and lysosomal degradation. Most intracellular bacteria encode one or two DUBs, which are often linkage-promiscuous or preferentially cleave K63-linked chains attached to bacteria or bacteria-containing vacuoles. By contrast, the respiratory pathogen Legionella pneumophila possesses a much larger number of DUB effectors, among them a K6-specific enzyme belonging to the OTU family and a M1-specific DUB uniquely found in this bacterium. Here, we report that the opportunistic pathogen Simkania negevensis, which is unrelated to Legionellabut has a similar lifestyle, encodes a similarly high number of DUBs, including M1- and K6-specific enzymes. The SimkaniaDUBs are highly diverse and include DUB classes never before seen in bacteria. Interestingly, the M1- and K6-specific DUBs of Legionella and Simkaniaare unrelated, suggesting that their acquisition happened independently. We have characterized the DUB activity of eight Simkania-encoded enzymes belonging to five different DUB classes. We also provide a structural basis for the M1-specificity of a Simkania DUB, which most likely evolved from a eukaryotic otubain-like precursor.

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“…We observed that RNF213 was recruited to a proportion of parasite containing vacuoles even in unstimulated cells, consistent with the fact that it is expressed at basal levels yet induced by IFN-g. Similarly, RNF213 has been shown to be recruited to vacuoles containing intracellular Salmonella (42), Listeria (46), and Chlamydia lacking the effector GarD (47), and to restrict their growth in the absence of IFN-g stimulation. We observed a slight increase in the growth of T. gondii in non-stimulated cells lacking RNF213; however, the major role for this factor was in IFN-g treated cells which completely lost growth inhibition in the absence of RNF213.…”

Section: Discussionmentioning

confidence: 99%

Molecular Basis for Interferon-mediated Pathogen Restriction in Human Cells

Matta

Kohio

Chandra

et al. 2022

Preprint

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To define novel mechanisms for cellular immunity to the intracellular pathogenToxoplasma gondii, we performed a genome-wide CRISPR loss-of-function screen to provide an unbiased assessment of genes important for IFN-γ-dependent growth restriction. We revealed a previously unknown role for the tumor suppressor NF-2/Merlin for maximum induction of Interferon Stimulated Genes (ISG), which are positively regulated by the transcription factor IRF-1. We then performed an additional focused ISG-targeted CRISPR screen that identified the host E3 ubiquitin ligase RNF213 as essential for IFN-γ mediated control ofT. gondii. RNF213 mediated ubiquitination of targets on the parasite-containing vacuole and growth restriction in response to IFN-γ in a variety of cell types, thus identifying a conserved factor that plays a prominent role in human cells. Surprisingly, growth inhibition did not require the autophagy protein ATG5, indicating that RNF213 initiates restriction independent of a non-canonical autophagy pathway that has previously been implicated in control ofT. gondii. RNF213 was also important for control of unrelated intracellular pathogens in human cells treated with IFN, as shown here forMycobacterium tuberculosisand Vesicular Stomatitis Virus. Collectively, our findings establish RNF213 as a critical component of cell-autonomous immunity to a broad spectrum of intracellular pathogens in human cells.

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The bacterial effector GarD shields Chlamydia trachomatis inclusions from RNF213-mediated ubiquitylation and destruction

Cited by 30 publications

References 82 publications

Homologues of the Chlamydia trachomatis and Chlamydia muridarum Inclusion Membrane Protein IncS Are Interchangeable for Early Development but Not for Inclusion Stability in the Late Developmental Cycle

Homologues of the Chlamydia trachomatis and Chlamydia muridarum Inclusion Membrane Protein IncS Are Interchangeable for Early Development but Not for Inclusion Stability in the Late Developmental Cycle

Unexpected functional and structural diversity in deubiquitinases of the Chlamydia-like bacterium Simkania negevensis

Molecular Basis for Interferon-mediated Pathogen Restriction in Human Cells

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