Phase separation drives RNA virus-induced activation of the NLRP6 inflammasome

Shen, Chen; Li, Runzhi; Negro, Roberto; Cheng, Jiewei; Vora, Setu M.; Fu, Tian‐Min; Wang, An Min; He, Kaixin; Andreeva, Liudmila; Gao, Pu; Tian, Zhigang; Flavell, Richard A.; Zhu, Shu; Wu, Hao

doi:10.1016/j.cell.2021.09.032

Cited by 146 publications

(142 citation statements)

References 45 publications

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“…In the intestine, NLRP6 regulates IL-18 production, cupped cell function, and flora homeostasis and collaborates with NLRP9 in defense against viruses [106]. In cup-ulocytes, NLRP6 was demonstrated to regulate mucus secretion in an inflammatory vesicle and autophagy-dependent manner to prevent invasion by intestinal bacteria [106,107]. Likewise, NLRP6 was found to prevent enterovirus infection, with increased viral load in knockout mice systemically infected with cerebral myocarditis virus or MNV in Nlrp6 knockout and control mice.…”

Section: Immune and Inflammatory Signaling Pathwaysmentioning

confidence: 99%

“…Ligands such as double-stranded RNA (dsRNA) produced by many viruses can interact with NLRP6 to induce liquid-liquid phase separation (LLPS). Mutations in a positively charged region of NLRP6 are essential for LLPS, which inhibits dsRNA-induced NLRP6 spot formation, GSDMD cleavage, and cell death, and impairs anti-microbial defenses in mice [107]. Mammalian IECs can sense the virus through MDA-5 and NLRP6 to activate type III IFN signaling or through TLR3 to activate NF-κB signaling [67].…”

Section: Immune and Inflammatory Signaling Pathwaysmentioning

confidence: 99%

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Bacterial and Viral Co-Infection in the Intestine: Competition Scenario and Their Effect on Host Immunity

Lian

Liu

et al. 2022

IJMS

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Bacteria and viruses are both important pathogens causing intestinal infections, and studies on their pathogenic mechanisms tend to focus on one pathogen alone. However, bacterial and viral co-infections occur frequently in clinical settings, and infection by one pathogen can affect the severity of infection by another pathogen, either directly or indirectly. The presence of synergistic or antagonistic effects of two pathogens in co-infection can affect disease progression to varying degrees. The triad of bacterial–viral–gut interactions involves multiple aspects of inflammatory and immune signaling, neuroimmunity, nutritional immunity, and the gut microbiome. In this review, we discussed the different scenarios triggered by different orders of bacterial and viral infections in the gut and summarized the possible mechanisms of synergy or antagonism involved in their co-infection. We also explored the regulatory mechanisms of bacterial–viral co-infection at the host intestinal immune interface from multiple perspectives.

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Section: Immune and Inflammatory Signaling Pathwaysmentioning

confidence: 99%

Section: Immune and Inflammatory Signaling Pathwaysmentioning

confidence: 99%

Bacterial and Viral Co-Infection in the Intestine: Competition Scenario and Their Effect on Host Immunity

Lian

Liu

et al. 2022

IJMS

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“…In a recent study, LTA and viral dsRNA have been described as promoting NLRP6 to form LLPS (Fig. 1b–d ), which questions the paradigm that NLRP6 active inflammasomes form structured oligomers that promote activation 43 . The polybasic region of NLRP6 located in the NACHT domain (350-354) is required for LLPS 43 .…”

Section: Structural Assembly Of the Nlrp6 Inflammasomementioning

confidence: 96%

“…e If ASC binds to NLRP6 oligomer, it induces a solid particle of inflammasome f that activates caspase-1 and/or caspase-11, which in turn processes GSDMD and results in plasma membrane pore formation and the release of pro-inflammatory cytokines and intracellular content. g If the NLRP6 inflammasome is not formed by interaction with ASC, NLRP6 in LLPS induces an alternative inflammasome-independent pathway by inducing interferon and interferon-stimulated genes 43 . …”

Section: Structural Assembly Of the Nlrp6 Inflammasomementioning

confidence: 99%

Physiological and pathophysiological functions of NLRP6: pro- and anti-inflammatory roles

2022

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The nucleotide-binding oligomerization and leucine-rich repeat receptor (NLR) protein family consists of important immune sensors that form inflammasomes, a cytosolic multi-protein platform that induces caspase-1 activation and is involved in different inflammatory pathologies. The NLR family pyrin domain containing 6 (NLRP6) is a receptor that can signal by forming inflammasomes, but which can also play an important role without forming inflammasomes. NLRP6 regulates intestinal homeostasis and inflammation, but also is involved in cancer, the nervous system or liver diseases, with both protective and deleterious consequences. In the present article, we review the different roles of NLRP6 in these processes and offer new insights into NLRP6 activation.

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“…Oxidized phospholipid (oxPAPC) binds to caspase-11 and elicits inflammasome activation in dendritic cells ( Zanoni et al, 2016 ) but competes with LPS binding and inhibits non-canonical inflammasome activation in macrophages conferring protection against Gram-negative bacterial sepsis ( Chu et al, 2018 ). Last, although less well-studied, the mechanisms of activation of other NLRP inflammasomes, namely NLRP2 ( Zhang et al, 2020 ), NLRP6 ( Shen et al, 2021 ), NLRP7 ( Radian et al, 2015 ), NLRP9 (reviewed in ( Mullins and Chen, 2021 )) and NLRP12 (reviewed in ( Tuladhar and Kanneganti, 2020 )) are emerging.…”

Section: A Snapshot Of the Inflammasomes: Structure And Activationmentioning

confidence: 99%

Inflammasomes in Cancer Progression and Anti-Tumor Immunity

Lillo

Saleh

2022

Front. Cell Dev. Biol.

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The inflammasomes are critical regulators of innate immunity, inflammation and cell death and have emerged as important regulators of cancer development and control. Inflammasomes are assembled by pattern recognition receptors (PRR) following the sensing of microbial- or danger-associated molecular patterns (MAMPs/DAMPs) and elicit inflammation through the oligomerization and activation of inflammatory caspases. These cysteinyl-aspartate proteases cleave the proinflammatory cytokines IL-1β and IL-18 into their biologically active mature form. The roles of the inflammasomes and associated pro-inflammatory cytokines vary greatly depending on the cancer type. Here we discuss recent studies highlighting contrasting roles of the inflammasome pathway in curbing versus promoting tumorigenesis. On one hand, the inflammasomes participate in stimulating anti-tumor immunity, but they have also been shown to contribute to immunosuppression or to directly promote tumor cell survival, proliferation, and metastasis. A better understanding of inflammasome functions in different cancers is thus critical for the design of novel cancer immunotherapies.

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Phase separation drives RNA virus-induced activation of the NLRP6 inflammasome

Cited by 146 publications

References 45 publications

Bacterial and Viral Co-Infection in the Intestine: Competition Scenario and Their Effect on Host Immunity

Bacterial and Viral Co-Infection in the Intestine: Competition Scenario and Their Effect on Host Immunity

Physiological and pathophysiological functions of NLRP6: pro- and anti-inflammatory roles

Inflammasomes in Cancer Progression and Anti-Tumor Immunity

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