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bioRxiv · 10.1101/578138

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

Raghawan, A. K.·Ramaswami, R.·Radha, V.·Swarup, G.
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Abstract

NLRC4 is an innate immune receptor, which upon detection of certain pathogens or internal distress signal, initiates caspase-1 mediated inflammatory response. A gain-of-function mutation, H443P in NLRC4, causes familial cold autoinflammatory syndrome (FCAS) characterized by cold-induced hyperactivation of caspase-1 and inflammation. Here, we show that heat shock cognate protein 70 (HSC70) complexes with NLRC4 and negatively regulates caspase-1 activation by NLRC4-H443P. Compared to NLRC4, the structurally altered NLRC4-H443P shows enhanced interaction with HSC70. Knockdown of HSC70 or inhibition of its ATPase activity enhances caspase-1 activation by NLRC4-H443P. Exposure to subnormal temperature resulted in reduced interaction of NLRC4-H443P with HSC70, and an increase in its ability to form ASC-specks and activate caspase-1. By demonstrating that HSC70 differentially interacts with NLRC4-H443P mutant in a temperature-dependent manner to regulate caspase-1 activation, we provide a mechanism for cold-induced inflammation seen in FCAS patients with NLRC4-H443P mutation.

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Raghawan, A. K., Ramaswami, R., Radha, V., Swarup, G.. 2019-03-15. HSC70 regulates cold-induced caspase-1 hyperactivation by an autoinflammation-causing mutant of cytoplasmic immune receptor NLRC4. https://doi.org/10.1101/578138

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