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

2019 ◽  
Author(s):  
Akhouri Kishore Raghawan ◽  
Rajashree Ramaswamy ◽  
Vegesna Radha ◽  
Ghanshyam Swarup
Keyword(s):  
Heat Shock ◽  
Innate Immune ◽  
Dependent Manner ◽  
Autoinflammatory Syndrome ◽  
Temperature Dependent ◽  
Familial Cold Autoinflammatory Syndrome ◽  
Immune Receptor ◽  
Caspase 1 ◽  
Heat Shock Cognate Protein ◽  
Cognate Protein

AbstractNLRC4 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.

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

2019 ◽  
Vol 116 (43) ◽  
pp. 21694-21703 ◽  
Author(s):  
Akhouri Kishore Raghawan ◽  
Rajashree Ramaswamy ◽  
Vegesna Radha ◽  
Ghanshyam Swarup
Keyword(s):  
Nucleotide Binding ◽  
Negative Regulator ◽  
Interleukin 1Β ◽  
Temperature Sensitive ◽  
Leucine Rich Repeat ◽  
Immune Receptor ◽  
Caspase 1 ◽  
Heat Shock Cognate Protein ◽  
Lower Temperature ◽  
Cognate Protein

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.

scholarly journals Exogenous heat shock cognate protein Hsc70 prevents axotomy-induced death of spinal sensory neurons

1996 ◽  
Vol 1 (3) ◽  
pp. 161 ◽  
Author(s):  
Lucien J. Houenou ◽  
Linxi Li ◽  
Ming Lei ◽  
Carol R. Kent ◽  
Michael Tytell
Keyword(s):  
Heat Shock ◽  
Sensory Neurons ◽  
Heat Shock Cognate Protein ◽  
Cognate Protein

Structural, thermodynamic and functional studies of human 71 kDa heat shock cognate protein (HSPA8/hHsc70)

2021 ◽  
Vol 1869 (12) ◽  
pp. 140719
Author(s):  
Noeli Soares Melo Silva ◽  
Luiz Fernando de Camargo Rodrigues ◽  
Paulo Roberto Dores-Silva ◽  
Carlos Alberto Montanari ◽  
Carlos Henrique Inácio Ramos ◽  
...  
Keyword(s):  
Heat Shock ◽  
Functional Studies ◽  
Heat Shock Cognate Protein ◽  
Cognate Protein

scholarly journals Exogenous Heat Shock Cognate Protein 70 Suppresses LPS-Induced Inflammation by Down-Regulating NF-κB through MAPK and MMP-2/-9 Pathways in Macrophages

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2124 ◽  
Author(s):  
Erna Sulistyowati ◽  
Mei-Yueh Lee ◽  
Lin-Chi Wu ◽  
Jong-Hau Hsu ◽  
Zen-Kong Dai ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Heat Shock ◽  
Critical Role ◽  
Matrix Metalloproteinase 2 ◽  
No Production ◽  
Raw 264.7 ◽  
Tnf Α ◽  
Heat Shock Cognate Protein ◽  
Anti Inflammatory ◽  
Cognate Protein

Heat shock cognate protein 70 (HSC70), a molecular chaperone, is constitutively expressed by mammalian cells to regulate various cellular functions. It is associated with many diseases and is a potential therapeutic target. Although HSC70 also possesses an anti-inflammatory action, the mechanism of this action remains unclear. This current study aimed to assess the anti-inflammatory effects of HSC70 in murine macrophages RAW 264.7 exposed to lipopolysaccharides (LPS) and to explain its pathways. Mouse macrophages (RAW 264.7) in 0.1 µg/mL LPS incubation were pretreated with recombinant HSC70 (rHSC70) and different assays (Griess assay, enzyme-linked immune assay/ELISA, electrophoretic mobility shift assay/EMSA, gelatin zymography, and Western blotting) were performed to determine whether rHSC70 blocks pro-inflammatory mediators. The findings showed that rHSC70 attenuated the nitric oxide (NO) generation, tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) expressions in LPS-stimulated RAW264.7 cells. In addition, rHSC70 preconditioning suppressed the activities and expressions of matrix metalloproteinase-2 (MMP-2) and MMP-9. Finally, rHSC70 diminished the nuclear translocation of nuclear factor-κB (NF-κB) and reduced the phosphorylation of extracellular-signal regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinases (MAPK), and phosphatidylinositol-3-kinase (PI3K/Akt). We demonstrate that rHSC70 preconditioning exerts its anti-inflammatory effects through NO production constriction; TNF-α, and IL-6 suppression following down-regulation of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), and MMP-2/MMP-9. Accordingly, it ameliorated the signal transduction of MAPKs, Akt/IκBα, and NF-κB pathways. Therefore, extracellular HSC70 plays a critical role in the innate immunity modulation and mechanisms of endogenous protective stimulation.

Psychophysiological stress induces heat shock cognate protein (HSC)70 mRNA in the cerebral cortex and stomach of rats

1995 ◽  
Vol 675 (1-2) ◽  
pp. 98-102 ◽  
Author(s):  
Shin Fukudo ◽  
Koji Abe ◽  
Michio Hongo ◽  
Atsushi Utsumi ◽  
Yasuto Itoyama
Keyword(s):  
Cerebral Cortex ◽  
Heat Shock ◽  
Psychophysiological Stress ◽  
Hsc 70 ◽  
Heat Shock Cognate Protein ◽  
Cognate Protein
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