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bioRxiv · 10.64898/2026.01.23.701331

TAK1 integrates the NLRP1 inflammasome into the innate immune response to double-stranded RNA

Corley, M. R.·Hyodo, A.·Toyoda, H. C.·Yonemitsu, M. A.·Chantharath, A.·Hyde, J. L.·Mitchell, P. S.
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Abstract

Innate immune recognition of double-stranded RNA (dsRNA) by germline-encoded receptors initiates antiviral defenses, including type I interferon (IFN) production. The inflammasome-forming sensor NLRP1 binds and is activated by dsRNA in a mitogen-activated protein kinase (MAPK) p38-dependent manner. How dsRNA initiates these events to induce NLRP1 inflammasome activation is unclear. Here we demonstrate that both exogenous and cellular dsRNA triggers NLRP1 inflammasome activation downstream of RIG-I/MDA5-MAVS and/or TLR3-TRIF signaling but is independent of type I IFN. In immortalized and primary human keratinocytes, we find that NLRP1 inflammasome activation by dsRNA, including during viral infection, requires the MAPK kinase kinase TAK1. Mechanistically, TAK1-dependent phosphorylation of the NLRP1 N-terminal disordered region is necessary and sufficient for inflammasome activation. Collectively, we reveal TAK1 as a novel activator of the NLRP1 inflammasome, functioning as a critical signaling hub linking NLRP1 to inflammatory responses in the context of viral infection and autoimmunity.

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Corley, M. R., Hyodo, A., Toyoda, H. C., Yonemitsu, M. A., Chantharath, A., Hyde, J. L., Mitchell, P. S.. 2026-01-25. TAK1 integrates the NLRP1 inflammasome into the innate immune response to double-stranded RNA. https://doi.org/10.64898/2026.01.23.701331

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