Shigella ubiquitin ligase IpaH7.8 targets gasdermin D for degradation to prevent pyroptosis and enable infection

Luchetti, Giovanni; Roncaioli, Justin L.; Chavez, Roberto A.; Schubert, Alexander F; Kofoed, Eric M.; Reja, Rohit; Cheung, Tommy K.; Liang, Yuxin; Webster, Joshua D.; Lehoux, Isabelle; Skippington, Elizabeth; Reeder, Janina; Haley, Benjamin; Tan, Man Wah; Rose, Christopher M.; Newton, Kim; Kayagaki, Nobuhiko; Vance, Russell E.; Dixit, Vishva M.

doi:10.1016/j.chom.2021.08.010

Cited by 126 publications

(100 citation statements)

References 59 publications

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“…A recent report indicates that GSDMB is capable of forming pores specifically in bacterial membranes, while sparing host cells, thereby promoting microbicidal activity and efficient clearance of infection (Hansen et al, 2021). Similarly, a role for GSDMDmediated pyroptosis of IECs in protecting host against intracellular oral pathogens has also been described (Luchetti et al, 2021). As most tumor-associated bacteria are localized within host cells (Nejman et al, 2020), these observations raise the tantalizing question as to whether GSDM activation in CRC might be influenced by the presence of specific bacterial strains that drive tumor-promoting functions.…”

Section: Influence Of the Microbiomementioning

confidence: 98%

Novel Insights Into the Interactions Between the Gut Microbiome, Inflammasomes, and Gasdermins During Colorectal Cancer

Privitera

Rana

Scaldaferri

et al. 2022

Front. Cell. Infect. Microbiol.

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Colorectal cancer (CRC) is one of the most prevalent and deadly forms of cancer in Western countries. Inflammation is a well-known driver of colonic carcinogenesis; however, its role in CRC extends beyond colitis-associated cancer. Over the last decades, numerous associations between intestinal dysbiosis and CRC have been identified, with more recent studies providing mechanistic evidence of a causative relationship. Nonetheless, much remains to be discovered regarding the precise implications of microbiome alterations in the pathogenesis of CRC. Research confirms the importance of a bidirectional crosstalk between the gut microbiome and the mucosal immune system in which inflammasomes, multiprotein complexes that can sense “danger signals,” serve as conduits by detecting microbial signals and activating innate immune responses, including the induction of microbicidal activities that can alter microbiome composition. Current evidence strongly supports an active role for this “inflammasome–microbiome axis” in the initiation and development of CRC. Furthermore, the gasdermin (GSDM) family of proteins, which are downstream effectors of the inflammasome that are primarily known for their role in pyroptosis, have been recently linked to CRC pathogenesis. These findings, however, do not come without controversy, as pyroptosis is reported to exert both anti- and protumorigenic functions. Furthermore, the multi-faceted interactions between GSDMs and the gut microbiome, as well as their importance in CRC, have only been superficially investigated. In this review, we summarize the existing literature supporting the importance of the inflammasome–microbiota axis, as well as the activation and function of GSDMs, to gain a better mechanistic understanding of CRC pathogenesis.

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Section: Influence Of the Microbiomementioning

confidence: 98%

Novel Insights Into the Interactions Between the Gut Microbiome, Inflammasomes, and Gasdermins During Colorectal Cancer

Privitera

Rana

Scaldaferri

et al. 2022

Front. Cell. Infect. Microbiol.

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“…This illustrates the potent defense conferred by pyroptosis and autophagy against pathogens that have intermediate or even high virulence potential, but which lack the ability to inhibit these defenses. Shigella is a pathogen with high virulence that additionally can inhibit these defenses ( 40 , 41 ). Shigella dysenteriae and Shigella flexneri cause the disease Shigellosis, which is characterized by hemorrhagic diarrhea and is particularly dangerous to young children ( 42 , 43 ).…”

Section: Shigella and Inhibition Of Pyroptosismentioning

confidence: 99%

“…OspC3 uses a unique biochemical reaction to catalyze the ADP-riboxanation of a critical arginine residue of caspase-11, which prevents activation of the caspase protease domain ( 46 ). Nevertheless, the innate immune system should still detect the Shigella T3SS via NAIP/NLRC4, activating caspase-1 and gasdermin D. However, Shigella can also inhibit gasdermin D with the T3SS effector IpaH7.8, which ubiquitinates both gasdermin D and gasdermin B to drive its proteasomal degradation ( 41 , 47 ). In the evolutionary battle between hosts and pathogens, OspC3 and IpaH7.8 put Shigella two steps ahead of cytosolic sensors that would cause pyroptosis and autophagy.…”

Section: Shigella and Inhibition Of Pyroptosismentioning

confidence: 99%

Autophagy May Allow a Cell to Forbear Pyroptosis When Confronted With Cytosol-Invasive Bacteria

Harvest

Miao

2022

Front. Immunol.

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Inflammatory caspases detect cytosol-invasive Gram-negative bacteria by monitoring for the presence of LPS in the cytosol. This should provide defense against the cytosol-invasive Burkholderia and Shigella species by lysing the infected cell via pyroptosis. However, recent evidence has shown caspase-11 and gasdermin D activation can result in two different outcomes: pyroptosis and autophagy. Burkholderia cepacia complex has the ability invade the cytosol but is unable to inhibit caspase-11 and gasdermin D. Yet instead of activating pyroptosis during infection with these bacteria, the autophagy pathway is stimulated through caspases and gasdermin D. In contrast, Burkholderia thailandensis can invade the cytosol where caspasae-11 and gasdermin D is activated but the result is pyroptosis of the infected cell. In this review we propose a hypothetical model to explain why autophagy would be the solution to kill one type of Burkholderia species, but another Burkholderia species is killed by pyroptosis. For pathogens with high virulence, pyroptosis is the only solution to kill bacteria. This explains why some pathogens, such as Shigella have evolved methods to inhibit caspase-11 and gasdermin D as well as autophagy. We also discuss similar regulatory steps that affect caspase-1 that may permit the cell to forbear undergoing pyroptosis after caspase-1 activates in response to bacteria with partially effective virulence factors.

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“…Instead of cleaving NLRP1B, IpaH7.8 directly ubiquitinates the N-terminus, thus targeting the protein for proteasomal degradation and releasing the bioactive C-terminal CARD domain ( Sandstrom et al, 2019 ). However, IpaH7.8 targets only mouse, and not human, NLRP1B ( Luchetti et al, 2021 ). Instead, IpaH7.8 ubiquitinates human GSDMD for degradation and blocks NLRC4 and caspase-mediated pyroptosis ( Luchetti et al, 2021 ).…”

Section: Regulation Of the Inflammasome And Fighting Back Against Eff...mentioning

confidence: 99%

“…However, IpaH7.8 targets only mouse, and not human, NLRP1B ( Luchetti et al, 2021 ). Instead, IpaH7.8 ubiquitinates human GSDMD for degradation and blocks NLRC4 and caspase-mediated pyroptosis ( Luchetti et al, 2021 ). Interestingly, IpaH7.8 has also recently been shown to ubiquitinate human gasdermin B (GSDMB) ( Hansen et al, 2021 ).…”

Section: Regulation Of the Inflammasome And Fighting Back Against Eff...mentioning

confidence: 99%

Bacterial Toxin and Effector Regulation of Intestinal Immune Signaling

Woida

Satchell

2022

Front. Cell Dev. Biol.

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The host immune response is highly effective to detect and clear infecting bacterial pathogens. Given the elaborate surveillance systems of the host, it is evident that in order to productively infect a host, the bacteria often coordinate virulence factors to fine-tune the host response during infection. These coordinated events can include either suppressing or activating the signaling pathways that control the immune response and thereby promote bacterial colonization and infection. This review will cover the surveillance and signaling systems for detection of bacteria in the intestine and a sample of the toxins and effectors that have been characterized that cirumvent these signaling pathways. These factors that promote infection and disease progression have also been redirected as tools or therapeutics. Thus, these toxins are enemies deployed to enhance infection, but can also be redeployed as allies to enable research and protect against infection.

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Shigella ubiquitin ligase IpaH7.8 targets gasdermin D for degradation to prevent pyroptosis and enable infection

Cited by 126 publications

References 59 publications

Novel Insights Into the Interactions Between the Gut Microbiome, Inflammasomes, and Gasdermins During Colorectal Cancer

Novel Insights Into the Interactions Between the Gut Microbiome, Inflammasomes, and Gasdermins During Colorectal Cancer

Autophagy May Allow a Cell to Forbear Pyroptosis When Confronted With Cytosol-Invasive Bacteria

Bacterial Toxin and Effector Regulation of Intestinal Immune Signaling

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