HSC70 regulates cold-induced caspase-1 hyperactivation by an autoinflammation-causing mutant of cytoplasmic immune receptor NLRC4
| Autor: | Rajashree Ramaswamy, Ghanshyam Swarup, Vegesna Radha, Akhouri Kishore Raghawan |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
animal structures Mutant Interleukin-1beta Caspase 1 Inflammation Apoptosis Immune receptor Cell Line 03 medical and health sciences 0302 clinical medicine Familial Cold Autoinflammatory Syndrome NLRC4 medicine Humans Caspase Multidisciplinary Innate immune system biology Hyperactivation Chemistry Calcium-Binding Proteins HSC70 Heat-Shock Proteins Inflammasome Cryopyrin-Associated Periodic Syndromes Cell biology CARD Signaling Adaptor Proteins Cold Temperature Enzyme Activation 030104 developmental biology HEK293 Cells PNAS Plus 030220 oncology & carcinogenesis Gain of Function Mutation biology.protein medicine.symptom medicine.drug |
| Popis: | NLRC4 [nucleotide-binding domain and leucine-rich repeat (NLR) family, caspase recruitment domain (CARD) containing 4] is an innate immune receptor, which, upon detection of certain pathogens or internal distress signals, initiates caspase-1-mediated interleukin-1β maturation and an inflammatory response. A gain-of-function mutation, H443P in NLRC4, causes familial cold autoinflammatory syndrome (FCAS) characterized by cold-induced hyperactivation of caspase-1, enhanced interleukin-1β maturation, and inflammation. Although the H443P mutant shows constitutive activity, the mechanism involved in hyperactivation of caspase-1 by NLRC4-H443P upon exposure of cells to lower temperature is not known. Here, we show that heat shock cognate protein 70 (HSC70) complexes with NLRC4 and negatively regulates caspase-1 activation by NLRC4-H443P in human cells. Compared with NLRC4, the structurally altered NLRC4-H443P shows enhanced interaction with HSC70. Nucleotide binding- and leucine-rich repeat domains of NLRC4, but not its CARD, can engage in complex formation with HSC70. Knockdown of HSC70 enhances apoptosis-associated speck-like protein containing a CARD (ASC)-speck formation and caspase-1 activation by NLRC4-H443P. Exposure to subnormal temperature results in reduced interaction of NLRC4-H443P with HSC70, and an increase in its ability to form ASC specks and activate caspase-1. Unlike the NLRC4-H443P mutant, another constitutively active mutant (NLRC4-V341A) associated with autoinflammatory diseases, but not FCAS, showed neither enhanced interaction with HSC70 nor an increase in inflammasome formation upon exposure to subnormal temperature. Our results identify HSC70 as a negative regulator of caspase-1 activation by the temperature-sensitive NLRC4-H443P mutant. We also show that low-temperature-induced hyperactivation of caspase-1 by NLRC4-H443P is due to loss of inhibition by HSC70. |
| Databáze: | OpenAIRE |
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