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EPS8 regulates an NLRP3 inflammasome-independent caspase-1 activation pathway in monosodium urate crystal-treated

Jen-Pin Chuang1, Chuan-Yu Kao2, Jenq-Chang Lee3

  • 1Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan, ROC; Department of Surgery, Puzi Hospital, Ministry of Health and Welfare, Chiayi, Taiwan, ROC.

Biochemical and Biophysical Research Communications
|June 30, 2020
PubMed

Insights

Epidermal growth factor receptor pathway substrate no. 8 (Eps8) is crucial for monosodium urate crystal-induced inflammation in gout. It activates caspase-1 independently of the NLRP3 inflammasome, revealing a new pathway in gout pathogenesis.

Area of Science:

  • Immunology
  • Cell Biology
  • Biochemistry

Background:

  • Gout is an inflammatory arthritis driven by monosodium urate (MSU) crystals.
  • NLRP3 inflammasome activation is key in gout's inflammatory response.
  • Mechanisms of caspase-1 activation in gout are not fully understood.

Purpose of the Study:

  • To investigate the role of Epidermal growth factor receptor pathway substrate no. 8 (Eps8) in MSU crystal-mediated caspase-1 activation.
  • To explore Eps8's function in macrophages lacking NLRP3 inflammasomes.

Main Methods:

  • Utilized RAW264.7 macrophages devoid of functional NLRP3 inflammasomes.
  • Performed kinetic studies to analyze protein expression timelines.
  • Investigated protein complex formation using co-immunoprecipitation.
  • Assessed the impact of Eps8 silencing on caspase-1 activation.

Main Results:

  • MSU crystals induced Eps8 expression prior to NLRP3 and caspase-1.
  • Actin cytoskeleton dynamics were essential for Eps8 induction and caspase-1 activation.
  • Eps8 silencing significantly reduced MSU crystal-induced NLRP3 expression and caspase-1 activation.
  • Eps8 formed complexes with pro-caspase-1 and mature caspase-1, but not NLRP3.

Conclusions:

  • Eps8 plays a critical role in MSU crystal-induced caspase-1 activation.
  • This activation occurs independently of the NLRP3 inflammasome.
  • Eps8 represents a novel target for gout treatment.
Keywords:
Caspase-1Eps8InflammasomeMacrophagesMonosodium urate

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