Human NLRP1 and NLRP3 interact to drive inflammation in inflammosomopathies and inflammatory diseases
Year: 2026
Type: preprint
Abstract: Inflammasomes are multiprotein complexes that form and activate after exposure to pathogenic microbes and host danger signals that trigger an inflammatory response. Although NLRP1 and NLRP3 inflammasomes share structural similarities and can be activated by similar stimuli, no evidence of heterotypic inflammasome assemblies has been reported. Here, we identify a unique interaction between NLRP1 and NLRP3 in human cells, forming a hybrid inflammasome, to drive inflammation. NLRP1 is essential for this hydrid inflammasome activation and NLRP3-mediated Caspase-1 activation and release of IL-1β and IL-18. The presence of the heterocomplex inflammasome was confirmed in blood samples from patients after kidney transplantation and is associated with inflammatory responses driven by NLRP3 and MEFV mutations that cause inflammasomopathies. Our findings reveal an unexpected level of intricacy in inflammasome composition, pinpointing hybrid targets that may pave the way for innovative pharmacological treatments for inflammatory disorders. Significance Statement Previous findings showed interactions between NLRP3 and NLRC4 or NLRP3 and NLRP11 showing that would be possible the interaction of the inflammasomes as supercomplexes and not working alone. Now, we show a new inflammasome heterocomplex inflammasome between NLRP1 and NLRP3 which is associated to the inflammatory profile in autoimmune diseases patietns and transplanted patients. These findings could open a new research topic for the design of dual inflammasomes inhibitors.
Institutions: Universidad Pablo de Olavide, Consejo Superior de Investigaciones Científicas, Instituto de Química Física Blas Cabrera, The University of Texas Southwestern Medical Center, Centro de Investigaciones Científicas Isla de la Cartuja, Instituto de Investigaciones Químicas, Universidad de Sevilla, Hospital Universitario Puerta del Mar, University of Glasgow, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Respiratorias
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: Fundación BBVA, Wellcome Trust, Ministerio de Ciencia, Innovación y Universidades, Ministerio de Ciencia e Innovación, Banco Bilbao Vizcaya Argentaria, Ministrstvo za Izobraževanje, Znanost in Šport, Junta de Andalucía, Instituto de Salud Carlos III, European Regional Development Fund, Agencia Estatal de Investigación, European Social Fund
OpenAlex ID: W7126038577