Small heterodimer partner interacts with NLRP3 and negatively regulates activation of the NLRP3 inflammasome

• Published in: Nature communications 2015-02, Vol.6 (1), p.6115-6115, Article 6115
• Main Authors: Yang, Chul-Su, Kim, Jwa-Jin, Kim, Tae Sung, Lee, Phil Young, Kim, Soo Yeon, Lee, Hye-Mi, Shin, Dong-Min, Nguyen, Loi T., Lee, Moo-Seung, Jin, Hyo Sun, Kim, Kwang-Kyu, Lee, Chul-Ho, Kim, Myung Hee, Park, Sung Goo, Kim, Jin-Man, Choi, Hueng-Sik, Jo, Eun-Kyeong
• Format: Article
• Language: English
• Subjects: 13; 631/250/256/2177; 631/250/262/2106/2517; 631/337/475/2290; 64; 64/60; 82; 82/58; 82/80; 96; 96/95; Animals; Apoptosis Regulatory Proteins - metabolism; CARD Signaling Adaptor Proteins; Carrier Proteins - metabolism; Caspase 1 - metabolism; Endoplasmic Reticulum - metabolism; Enzyme Activation; HEK293 Cells; Homeostasis; Humanities and Social Sciences; Humans; Inflammasomes - metabolism; Interleukin-1beta - metabolism; Mice, Inbred C57BL; Mitochondria - metabolism; multidisciplinary; NLR Family, Pyrin Domain-Containing 3 Protein; Protein Binding; Protein Transport; Receptors, Cytoplasmic and Nuclear - deficiency; Receptors, Cytoplasmic and Nuclear - metabolism; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms7115

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.