The molecular activation mechanism of inflammasomes remains largely unknown in spite of their well-studied function in immune response and disease development. Researchers from Institute of Biochemistry and Cell Biology (SIBCB), Shanghai Institutes for Biological Sciences (SIBS) of Chinese Academy of Sciences revealed the novel function of β-arrestin1 in regulation of inflammasome activation.
β-arrestins are multifunctional proteins that play critical roles in G protein-coupled receptor signaling pathway. β-arrestin1 is also involved in autoimmune diseases such as experimental autoimmune encephalomyelitis. To explore the function of β-arrestin1 in inflammasome activation, MAO Kairui, CHEN Shuzhen, WANG Yan and their colleagues, led by Prof. SUN Bing and Prof. PEI Gang at SIBCB, SIBS, carried out a series of experiments using β-arrestin1-deficient mice. They found that in β-arrestin1-deficient peritoneal macrophages (PMs), nucleotide-binding domain and leucine-rich repeat containing family pyrin domain–containing 3 (NLRP3) and nucleotide-binding domain and leucine-rich repeat containing family CARD domain–containing protein 4 (NLRC4) inflammasome activation were strikingly dampened.
With crosslinking assay and immunofluorescence assay, β-arrestin1 was found to promote NLRP3 and NLRC4-induced apoptosis-associated speck-like protein containing a CARD (ASC) pyroptosome formation. Further mechanistic study revealed β-arrestin1 could specifically interact with NLRP3 and NLRC4, and enhance their self-oligomerization.
In vivo, β-arrestin1 was involved in MSU-induced peritonitis model, by promoting IL-1β production and neutrophils influx. During Salmonella typhimurium infection, which causes severe inflammation through NLRC4 inflammasome activation, β-arrestin1 deficiency played a protective role and modulated IL-1β production as well.
This study suggests the positive role of β-arrestin1 in regulating NLRP3 and NLRC4 inflammasomes, which may be a potential target in the treatment of IL-1β-associated auto-inflammatory diseases.
This work entitled “β-arrestin1 is critical for the full activation of NLRP3 and NLRC4 inflammasomes” was published on line in The Journal of Immunology on Jan 12, 2015. This study was supported by grants from the National Natural Science Foundation of China and the 973 programs.
CONTACT:
SUN Bing, Principal Investigator
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Shanghai 200031, China.
E-mail: bsun@sibs.ac.cn
Phone: +8621-54921375
Fig. A: NLRP3 inflammasome mediated-IL-1β production was impaired in β-arrestin1-deficient PMs; B-C: NLRC4 inflammasome mediated-IL-1β production was impaired in β-arrestin1-deficient PMs; D: Activation of absent in melanoma 2 inflammasome was intact with β-arrestin1 deficiency. PMs, peritoneal macrophages. (Image provided by Prof. SUN Bing’s group)
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