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A cereblon-based (CRBN) glue degrader of NEK7 regulates NLRP3 inflammasome in a context-dependent manner

ABSTRACT: Aberrant NLRP3 inflammasome activation is linked to many inflammatory diseases, driving the search for therapeutics inhibiting this pathway. NEK7 is proposed to mediate NLRP3 inflammasome assembly and activation by bridging adjacent NLRP3 subunits. Hence, reduction of NEK7 protein may block NLRP3 activation. We identified NK7-902, a potent and selective CRBN glue degrader of NEK7. NK7-902 degraded NEK7 in human immune cells and whole blood. However, full NEK7 degradation completely blocked NLRP3-dependent IL-1β release in vitro only in certain donors and experimental conditions. Unlike most CRBN glue degraders, NK7-902 effectively degraded NEK7 in murine cells and inhibited IL-1β release in mouse in vivo. By contrast, oral administration of NK7-902 in cynomolgus monkey caused long-lasting NEK7 degradation but only transiently blocked IL-1β in blood. These findings suggest NEK7 contributes to but is not absolutely required for NLRP3 activation in monkeys and humans.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Spleen, Monocyte, Stem Cell

SUBMITTER: Andreas Hofmann

LAB HEAD: Andreas Josef

PROVIDER: PXD057229 | Pride | 2025-06-18

REPOSITORIES: Pride

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			Action	DRS
	PXP0809_ATI9NP3_NEK7_24Fr_UP19_PD24.mzML	Mzml
	PXP0809_ATI9NP3_NEK7_24Fr_UP19_PD24.mzid.gz	Mzid
	PXP0809_ATI9NP3_NEK7_24Fr_UP19_PD24.pdResult	Other
	PXP0809_ATI9NP3_NEK7_Fr01_BLU2_2019_0829.raw	Raw
	PXP0809_ATI9NP3_NEK7_Fr02_BLU2_2019_0830.raw	Raw

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Project description:BACKGROUND: Cryopyrin-Associated Periodic Syndrome (CAPS) is an autoinflammatory condition consequence of monoallelic variants in the NLRP3 gene that exacerbate IL-1β production. These variants are gain-of-function, but the exact regulatory mechanism of the NLRP3 CAPS-inflammasome is not well yet understood. It is considered as a hypersensitive inflammasome triggered by cell priming, but patients with CAPS and animal disease models present inflammatory flares in the absence of external triggers.OBJECTIVES: To study the regulation and activation of the NLRP3 inflammasome in CAPS.METHODS: CAPS derived blood samples and genetically modified macrophages expressing different NLRP3 CAPS-associated variants were used to assess NLRP3 function dissociated from cell priming and cell metabolism.RESULTS: We found that CAPS-associated variants constitutively result in active NLRP3 inflammasomes, that induce a basal cleavage of gasdermin D, IL-18 release and pyroptosis. The constitutive active NLRP3 inflammasome was blocked by MCC950 and was dependent on NLRP3 expression level, being further regulated by deubiquitination. We also showed that activation of NF-κB with lipopolysaccharide or other endogenous host-derived molecules (palmitate, S100A9 or IL-6) further modulated the activation of the NLRP3 CAPS inflammasome and expanded the repertoire of molecules secreted from CAPS macrophages to IL-1β, IL-1α, HMGB1, cystatin B and the P2X7 receptor, identifying novel proteins involved in CAPS pathogenesis. NLRP3 inflammasomes with CAPS associated variants affected the immunometabolism of the myeloid compartment and impaired glycolysis.CONCLUSIONS: These findings demonstrate that NLRP3 CAPS-associated variants form a constitutive active inflammasome that induce basal pyroptosis and IL-18 release without cell priming, suggesting a priming-independent mechanism for the initiation of CAPS flares characterized with a profound affection in the immunometabolism.

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A cereblon-based (CRBN) glue degrader of NEK7 regulates NLRP3 inflammasome in a context-dependent manner

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