Ubiquitin systems mark pathogen-containing vacuoles as targets for host defense by guanylate binding proteins

Haldar, Arun Kumar; Foltz, Clémence; Finethy, Ryan; Piro, Anthony S.; Feeley, Eric M.; Pilla-Moffett, Danielle M; Komatsu, Masaaki; Frickel, Eva‐Maria; Coers, Jörn

doi:10.1073/pnas.1515966112

Cited by 145 publications

(259 citation statements)

References 68 publications

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“…In support of our finding, TRAF6 was found to be translocated into pathogen-containing vacuoles (PVs) (45) and was involved in the ubiquitin-dependent labeling of PVs, which provide a safe haven for many intracellular bacterial pathogens (46). In conclusion, we have described here a mechanism by which S. Typhimurium T3SS effectors broaden their functions through the activation of host proteins in a ubiquitination-dependent manner to modulate host transcriptional responses so as to adapt host cells to the intracellular replication of bacteria.…”

Section: Traf6 Ubiquitination Of Stat3supporting

confidence: 80%

Tumor Necrosis Factor Receptor-Associated Factor 6 (TRAF6) Mediates Ubiquitination-Dependent STAT3 Activation upon Salmonella enterica Serovar Typhimurium Infection

et al. 2017

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Salmonella enterica serovar Typhimurium can inject effector proteins into host cells via type III secretion systems (T3SSs). These effector proteins modulate a variety of host transcriptional responses to facilitate bacterial growth and survival. Here we show that infection of host cells with S. Typhimurium specifically induces the ubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6). This TRAF6 ubiquitination is triggered by the Salmonella pathogenicity island 1 (SPI-1) T3SS effectors SopB and SopE2. We also demonstrate that TRAF6 is involved in the SopB/ SopE2-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3), a signaling event conducive to the intracellular growth of S. Typhimurium. Specifically, TRAF6 mediates lysine-63 ubiquitination within the Src homology 2 (SH2) domain of STAT3, which is an essential step for STAT3 membrane recruitment and subsequent phosphorylation in response to S. Typhimurium infection. TRAF6 ubiquitination participates in STAT3 phosphorylation rather than serving as only a hallmark of E3 ubiquitin ligase activation. Our results reveal a novel strategy in which S. Typhimurium T3SS effectors broaden their functions through the activation of host proteins in a ubiquitination-dependent manner to manipulate host cells into becoming a Salmonella-friendly zone.KEYWORDS Salmonella enterica serovar Typhimurium, TRAF6, ubiquitination, STAT3, Salmonella effectors I nfection with bacterial pathogens often induces host inflammatory responses (1), which are initiated by the recognition of microbial products, collectively known as pathogen-associated molecular patterns (PAMPs). PAMPs are recognized by Toll-like receptors (TLRs) or cytosolic NOD-like receptors (NLRs) (1, 2), which activate nuclear factor B (NF-B) and mitogen-activated protein kinases (MAPKs) and induce the production of proinflammatory cytokines critical for host defenses (3, 4). To overcome host defenses, some pathogens have developed strategies to dampen the host innate immune response by inactivating MAPKs or NF-B signaling. For instance, the Shigella flexneri phosphothreonine lyase OspF, which is injected into host cells by a type III secretion system (T3SS), inactivates the innate immune response by dephosphorylating MAPKs (5). The Yersinia protein YopJ/YopP, a T3SS effector protein containing both

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Section: Traf6 Ubiquitination Of Stat3supporting

confidence: 80%

Tumor Necrosis Factor Receptor-Associated Factor 6 (TRAF6) Mediates Ubiquitination-Dependent STAT3 Activation upon Salmonella enterica Serovar Typhimurium Infection

et al. 2017

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“…1E). More detailed studies on the mechanism of GBP binding to C. trachomatis inclusion membranes confirmed these observations (46). Together, these data indicated that C. muridarum barred GBPs from binding to its surrounding inclusion membrane, an activity likely underlying the observed resistance of C. muridarum to GBP-mediated bactericidal or bacteriostatic effects that help eliminate infections with C. trachomatis.…”

Section: Chlamydia Muridarum Is Resistant To Gbp-mediated Cell-autonosupporting

confidence: 52%

Guanylate Binding Proteins Enable Rapid Activation of Canonical and Noncanonical Inflammasomes in Chlamydia-Infected Macrophages

et al. 2015

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g Interferon (IFN)-inducible guanylate binding proteins (GBPs) mediate cell-autonomous host resistance to bacterial pathogens and promote inflammasome activation. The prevailing model postulates that these two GBP-controlled activities are directly linked through GBP-dependent vacuolar lysis. It was proposed that the rupture of pathogen-containing vacuoles (PVs) by GBPs destroyed the microbial refuge and simultaneously contaminated the host cell cytosol with microbial activators of inflammasomes. Here, we demonstrate that GBP-mediated host resistance and GBP-mediated inflammatory responses can be uncoupled. We show that PVs formed by the rodent pathogen Chlamydia muridarum, so-called inclusions, remain free of GBPs and that C. muridarum is impervious to GBP-mediated restrictions on bacterial growth. Although GBPs neither bind to C. muridarum inclusions nor restrict C. muridarum growth, we find that GBPs promote inflammasome activation in C. muridaruminfected macrophages. We demonstrate that C. muridarum infections induce GBP-dependent pyroptosis through both caspase-11-dependent noncanonical and caspase-1-dependent canonical inflammasomes. Among canonical inflammasomes, we find that C. muridarum and the human pathogen Chlamydia trachomatis activate not only NLRP3 but also AIM2. Our data show that GBPs support fast-kinetics processing and secretion of interleukin-1␤ (IL-1␤) and IL-18 by the NLRP3 inflammasome but are dispensable for the secretion of the same cytokines at later times postinfection. Because IFN-␥ fails to induce IL-1␤ transcription, GBP-dependent fast-kinetics inflammasome activation can drive the preferential processing of constitutively expressed IL-18 in IFN-␥-primed macrophages in the absence of prior Toll-like receptor stimulation. Together, our results reveal that GBPs control the kinetics of inflammasome activation and thereby shape macrophage responses to Chlamydia infections.

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“…We previously demonstrated that IRGs are essential for targeting GBPs to Toxoplasma-and Chlamydia-containing vacuoles (20,21). In this study, we describe an IRG-independent pathway by which GBPs are delivered to PVs.…”

Section: Significancementioning

confidence: 70%

“…Although IRGs and GBPs can combat intracellular infections cooperatively, mounting evidence suggests that these two protein families also execute unique cellular functions independent of one another (16). For example, IRGs facilitate the delivery of ubiquitin E3 ligases to Toxoplasma-and Chlamydia-containing vacuoles independent of GBPs (21,22). GBPs, on the contrary, were reported to control the deposition of the NADPH oxidase NOX2 at Mycobacterium-containing phagosomes independent of IRGs (24).…”

Section: Significancementioning

confidence: 99%

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Galectin-3 directs antimicrobial guanylate binding proteins to vacuoles furnished with bacterial secretion systems

Feeley

Pilla-Moffett

Zwack

et al. 2017

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

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125

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Many invasive bacteria establish pathogen-containing vacuoles (PVs) as intracellular niches for microbial growth. Immunity to these infections is dependent on the ability of host cells to recognize PVs as targets for host defense. The delivery of several host defense proteins to PVs is controlled by IFN-inducible guanylate binding proteins (GBPs), which themselves dock to PVs through poorly characterized mechanisms. Here, we demonstrate that GBPs detect the presence of bacterial protein secretion systems as “patterns of pathogenesis” associated with PVs. We report that the delivery of GBP2 to Legionella-containing vacuoles is dependent on the bacterial Dot/Icm secretion system, whereas the delivery of GBP2 to Yersinia-containing vacuoles (YCVs) requires hypersecretion of Yersinia translocon proteins. We show that the presence of bacterial secretion systems directs cytosolic carbohydrate-binding protein Galectin-3 to PVs and that the delivery of GBP1 and GBP2 to Legionella-containing vacuoles or YCVs is substantially diminished in Galectin-3–deficient cells. Our results illustrate that insertion of bacterial secretion systems into PV membranes stimulates Galectin-3–dependent recruitment of antimicrobial GBPs to PVs as part of a coordinated host defense program.

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Ubiquitin systems mark pathogen-containing vacuoles as targets for host defense by guanylate binding proteins

Cited by 145 publications

References 68 publications

Tumor Necrosis Factor Receptor-Associated Factor 6 (TRAF6) Mediates Ubiquitination-Dependent STAT3 Activation upon Salmonella enterica Serovar Typhimurium Infection

Tumor Necrosis Factor Receptor-Associated Factor 6 (TRAF6) Mediates Ubiquitination-Dependent STAT3 Activation upon Salmonella enterica Serovar Typhimurium Infection

Guanylate Binding Proteins Enable Rapid Activation of Canonical and Noncanonical Inflammasomes in Chlamydia-Infected Macrophages

Galectin-3 directs antimicrobial guanylate binding proteins to vacuoles furnished with bacterial secretion systems

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