Small-molecule GSDMD agonism in tumors stimulates antitumor immunity without toxicity.

Gasdermin-mediated inflammatory cell death (pyroptosis) can activate protective immunity in immunologically cold tumors. Here, we performed a high-throughput screen for compounds that could activate gasdermin D (GSDMD), which is expressed widely in tumors. We identified 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (DMB) as a direct and selective GSDMD agonist that activates GSDMD pore formation and pyroptosis without cleaving GSDMD.

FcγR-mediated SARS-CoV-2 infection of monocytes activates inflammation.

SARS-CoV-2 can cause acute respiratory distress and death in some patients. Although severe COVID-19 is linked to substantial inflammation, how SARS-CoV-2 triggers inflammation is not clear. Monocytes and macrophages are sentinel cells that sense invasive infection to form inflammasomes that activate caspase-1 and gasdermin D, leading to inflammatory death (pyroptosis) and the release of potent inflammatory mediators.

Targeting stem-loop 1 of the SARS-CoV-2 5' UTR to suppress viral translation and Nsp1 evasion.

SARS-CoV-2 is a highly pathogenic virus that evades antiviral immunity by interfering with host protein synthesis, mRNA stability, and protein trafficking. The SARS-CoV-2 nonstructural protein 1 (Nsp1) uses its C-terminal domain to block the messenger RNA (mRNA) entry channel of the 40S ribosome to inhibit host protein synthesis. However, how SARS-CoV-2 circumvents Nsp1-mediated suppression for viral protein synthesis and if the mechanism can be targeted therapeutically remain unclear.

Inflammasome Activation and Pyroptosis via a Lipid-regulated SIRT1-p53-ASC Axis in Macrophages From Male Mice and Humans.

Obesity-linked diabetes is associated with accumulation of proinflammatory macrophages into adipose tissue leading to inflammasome activation and pyroptotic secretion of interleukin (IL)-1β and IL-18. Targeting fatty acid binding protein 4 (FABP4) uncouples obesity from inflammation, attenuates characteristics of type 2 diabetes and is mechanistically linked to the cellular accumulation of monounsaturated fatty acids in macrophages. Herein we show that pharmacologic inhibition or genetic deletion of FABP4 activates silent mating type information regulation 2 homolog 1 (SIRT1) and deacetylates its downstream targets p53 and signal transducer and activator of transcription 3 (STAT3).

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

NLRP6 is important in host defense by inducing functional outcomes including inflammasome activation and interferon production. Here, we show that NLRP6 undergoes liquid-liquid phase separation (LLPS) upon interaction with double-stranded RNA (dsRNA) in vitro and in cells, and an intrinsically disordered poly-lysine sequence (K350-354) of NLRP6 is important for multivalent interactions, phase separation, and inflammasome activation. Nlrp6-deficient or Nlrp6 mutant mice show reduced inflammasome activation upon mouse hepatitis virus or rotavirus infection, and in steady state stimulated by intestinal microbiota, implicating NLRP6 LLPS in anti-microbial immunity.

SARS-CoV-2 infects blood monocytes to activate NLRP3 and AIM2 inflammasomes, pyroptosis and cytokine release.

SARS-CoV-2 causes acute respiratory distress that can progress to multiorgan failure and death in a minority of patients. Although severe COVID-19 disease is linked to exuberant inflammation, how SARS-CoV-2 triggers inflammation is not understood. Monocytes and macrophages are sentinel immune cells in the blood and tissue, respectively, that sense invasive infection to form inflammasomes that activate caspase-1 and gasdermin D (GSDMD) pores, leading to inflammatory death (pyroptosis) and processing and release of IL-1 family cytokines, potent inflammatory mediators.

Inflammasome activation at the crux of severe COVID-19.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), results in life-threatening disease in a minority of patients, especially elderly people and those with co-morbidities such as obesity and diabetes. Severe disease is characterized by dysregulated cytokine release, pneumonia and acute lung injury, which can rapidly progress to acute respiratory distress syndrome, disseminated intravascular coagulation, multisystem failure and death. However, a mechanistic understanding of COVID-19 progression remains unclear.

Structures and functions of the inflammasome engine.

Inflammasomes are molecular machines that carry out inflammatory responses on challenges by pathogens and endogenous dangers. Dysregulation of inflammasome assembly and regulation is associated with numerous human diseases from autoimmunity to cancer. In recent years, significant advances have been made in understanding the mechanism of inflammasome signaling using structural approaches.

Gasdermin D pore structure reveals preferential release of mature interleukin-1.

As organelles of the innate immune system, inflammasomes activate caspase-1 and other inflammatory caspases that cleave gasdermin D (GSDMD). Caspase-1 also cleaves inactive precursors of the interleukin (IL)-1 family to generate mature cytokines such as IL-1β and IL-18. Cleaved GSDMD forms transmembrane pores to enable the release of IL-1 and to drive cell lysis through pyroptosis.

SARS-CoV-2 infects blood monocytes to activate NLRP3 and AIM2 inflammasomes, pyroptosis and cytokine release.

Unlabelled: SARS-CoV-2 causes acute respiratory distress that can progress to multiorgan failure and death in some patients. Although severe COVID-19 disease is linked to exuberant inflammation, how SARS-CoV-2 triggers inflammation is not understood. Monocytes are sentinel blood cells that sense invasive infection to form inflammasomes that activate caspase-1 and gasdermin D (GSDMD) pores, leading to inflammatory death (pyroptosis) and processing and release of IL-1 family cytokines, potent inflammatory mediators.

Centrosomes are required for proper β-catenin processing and Wnt response.

The Wnt/β-catenin signaling pathway is central to metazoan development and routinely dysregulated in cancer. Wnt/β-catenin signaling initiates transcriptional reprogramming upon stabilization of the transcription factor β-catenin, which is otherwise posttranslationally processed by a destruction complex and degraded by the proteasome. Since various Wnt signaling components are enriched at centrosomes, we examined the functional contribution of centrosomes to Wnt signaling, β-catenin regulation, and posttranslational modifications.

Higher-order assemblies in innate immune and inflammatory signaling: A general principle in cell biology.

Higher-order supramolecular complexes-dubbed signalosomes carry out key signaling and effector functions in innate immunity and inflammation. In this review, we present several recently discovered signalosomes that are formed either by stable protein-protein interactions or by dynamic liquid-liquid phase separation. Structural features of these signalosomes are highlighted to elucidate their functions and biological insights.

The benefits of local depletion: The centrosome as a scaffold for ubiquitin-proteasome-mediated degradation.

The centrosome is the major microtubule-organizing center in animal cells but is dispensable for proper microtubule spindle formation in many biological contexts and is thus thought to fulfill additional functions. Recent observations suggest that the centrosome acts as a scaffold for proteasomal degradation in the cell to regulate a variety of biological processes including cell fate acquisition, cell cycle control, stress response, and cell morphogenesis. Here, we review the body of studies indicating a role for the centrosome in promoting proteasomal degradation of ubiquitin-proteasome substrates and explore the functional relevance of this system in different biological contexts.