Small heterodimer partner interacts with NLRP3 and negatively regulatesactivation of the NLRP3 inflammasome
| Autor: | Phil Young Lee, Eun-Kyeong Jo, Soo Yeon Kim, Sung Goo Park, Jin-Man Kim, Loi T. Nguyen, Myung Hee Kim, Hye-Mi Lee, Chul-Ho Lee, Hyo Sun Jin, Hueng-Sik Choi, Moo-Seung Lee, Tae Sung Kim, J.W. Kim, Kwang-Kyu Kim, Dong-Min Shin, Chul-Su Yang |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
animal structures
Inflammasomes Interleukin-1beta Receptors Cytoplasmic and Nuclear General Physics and Astronomy chemical and pharmacologic phenomena Biology Endoplasmic Reticulum Article General Biochemistry Genetics and Molecular Biology Proinflammatory cytokine NLR Family Pyrin Domain-Containing 3 Protein medicine Animals Homeostasis Humans Secretion Multidisciplinary integumentary system Endoplasmic reticulum Caspase 1 HEK 293 cells Inflammasome hemic and immune systems General Chemistry Mitochondria Transport protein Cell biology CARD Signaling Adaptor Proteins Enzyme Activation Mice Inbred C57BL Protein Transport HEK293 Cells Nuclear receptor Small heterodimer partner Apoptosis Regulatory Proteins Carrier Proteins Protein Binding medicine.drug |
| Zdroj: | NATURE COMMUNICATIONS(6) Nature Communications |
| Popis: | Excessive activation of the NLRP3 inflammasome results in damaging inflammation, yet the regulators of this process remain poorly defined. Herein, we show that the orphan nuclear receptor small heterodimer partner (SHP) is a negative regulator of NLRP3 inflammasome activation. NLRP3 inflammasome activation leads to an interaction between SHP and NLRP3, proteins that are both recruited to mitochondria. Overexpression of SHP competitively inhibits binding of NLRP3 to apoptosis-associated speck-like protein containing a CARD (ASC). SHP deficiency results in increased secretion of proinflammatory cytokines IL-1β and IL-18, and excessive pathologic responses typically observed in mouse models of kidney tubular necrosis and peritoneal gout. Notably, the loss of SHP results in accumulation of damaged mitochondria and a sustained interaction between NLRP3 and ASC in the endoplasmic reticulum. These data are suggestive of a role for SHP in controlling NLRP3 inflammasome activation through a mechanism involving interaction with NLRP3 and maintenance of mitochondrial homeostasis. Excessive NLRP3 inflammasome activation underlies inflammatory diseases such as gout. Here the authors show that orphan nuclear receptor small heterodimer partner protein (SHP) negatively regulates NLRP3, and its loss leads to accumulation of damaged mitochondria and gout-like immunopathology. |
| Databáze: | OpenAIRE |
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