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Significance Immune receptor NLRC4 mediates caspase-1 activation upon stimulation. Mutations of NLRC4 and other cytoplasmic immune receptors cause familial cold autoinflammatory syndrome (FCAS). Individuals carrying the NLRC4-H443P mutation show exacerbated inflammation upon exposure to a cold environment due to caspase-1 hyperactivation. The mechanism of cold-induced hyperactivation of caspase-1 by none of the FCAS-causing mutants is known. We identified heat shock cognate protein 70 (HSC70) as an interacting partner of NLRC4-H443P that negatively regulates caspase-1 activation. Exposure to subnormal temperature reduces interaction of H443P with HSC70, causing caspase-1 hyperactivation. We provide a molecular mechanism for exacerbation of inflammation induced by cold temperature in individuals carrying the NLRC4-H443P mutation, which might have broader implications for temperature regulation of FCAS-causing mutations of other receptors.

HSC70 regulates cold-induced caspase-1 hyperactivation by an autoinflammation-causing mutant of cytoplasmic immune receptor NLRC4