LRRFIP2 negatively regulates NLRP3 inflammasome activation in macrophages by promoting Flightless-I-mediated caspase-1 inhibition

被引：77

作者：

Jin, Jing ^{[1
,2
,3
]}

Yu, Qian ^{[2
,3
]}

Han, Chaofeng ^{[2
,3
]}

Hu, Xiang ^{[4
,5
]}

Xu, Sheng ^{[2
,3
]}

Wang, Qingqing ^{[1
]}

Wang, Jianli ^{[1
]}

Li, Nan ^{[2
,3
]}

Cao, Xuetao ^{[1
,2
,3
,4
,5
]}

机构：

[1] Zhejiang Univ, Inst Immunol, Sch Med, Hangzhou 310058, Zhejiang, Peoples R China

[2] Second Mil Med Univ, Natl Key Lab Med Immunol, Shanghai 200433, Peoples R China

[3] Second Mil Med Univ, Inst Immunol, Shanghai 200433, Peoples R China

[4] Chinese Acad Med Sci, Natl Key Lab Med Mol Biol, Beijing 100005, Peoples R China

[5] Chinese Acad Med Sci, Dept Immunol, Beijing 100005, Peoples R China

来源：

NATURE COMMUNICATIONS | 2013年 / 4卷

基金：

中国国家自然科学基金;

关键词：

LEUCINE-RICH REPEAT; IDENTIFICATION; PROTEINS; INNATE; RNA; INTERFERON; RESPONSES; PARTNERS; IMMUNITY; BETA;

D O I：

10.1038/ncomms3075

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The NLRP3 inflammasome is the most characterized inflammasome activated by cellular infection or stress, which is responsible for the maturation of proinflammatory cytokines IL-1 beta and IL-18. The precise molecular mechanism for negative regulation of NLRP3 inflammasome activation needs to be further defined. Here we identify leucine-rich repeat Fli-I-interacting protein 2 (LRRFIP2) as an NLRP3-associated protein and an inhibitor for NLRP3 inflammasome activation. LRRFIP2 binds to NLRP3 via its N terminus upon NLRP3 inflammasome activation, and also interacts with Flightless-I, a pseudosubstrate of caspase-1, via its Coil motif. Knockdown of Flightless-I significantly promotes NLRP3 inflammasome activation. LRRFIP2 enhances the interaction between Flightless-I and caspase-1, facilitating the inhibitory effect of Flightless-I on caspase-1 activation. Furthermore, silencing of Flightless-I abrogates the inhibitory effect of LRRFIP2 on NLRP3 inflammasome. These data demonstrate that LRRFIP2 inhibits NLRP3 inflammasome activation by recruiting the caspase-1 inhibitor Flightless-I, thus outlining a new mechanism for negative regulation of NLRP3 inflammasome.

引用

页数：8

共 33 条

[1] Bcl-2 and Bcl-XL regulate proinf lammatory caspase-1 activation by interaction with NALP1 [J].

Bruey, Jean-Marie ;

Bruey-Sedano, Nathalie ;

Luciano, Frederic ;

Zhai, Dayong ;

Balpai, Ruchi ;

Xu, Chunyan ;

Kress, Christina L. ;

Bailly-Maitre, Beatrice ;

Li, Xiaoqing ;

Osterman, Andrei ;

Matsuzawa, Shu-ichi ;

Terskikh, Alexey V. ;

Faustin, Benjamin ;

Reed, John C. .

CELL, 2007, 129 (01) :45-56

[2] Fliih, a gelsolin-related cytoskeletal regulator essential for early mammalian embryonic development [J].

Campbell, HD ;

Fountain, S ;

McLennan, IS ;

Berven, LA ;

Crouch, MF ;

Davy, DA ;

Hooper, JA ;

Waterford, K ;

Chen, KS ;

Lupski, JR ;

Ledermann, B ;

Young, IG ;

Matthaei, KI .

MOLECULAR AND CELLULAR BIOLOGY, 2002, 22 (10) :3518-3526

[3] Induction of Siglec-G by RNA Viruses Inhibits the Innate Immune Response by Promoting RIG-I Degradation [J].

Chen, Weilin ;

Han, Chaofeng ;

Xie, Bin ;

Hu, Xiang ;

Yu, Qian ;

Shi, Liyun ;

Wang, Qingqing ;

Li, Dongling ;

Wang, Jianli ;

Zheng, Pan ;

Liu, Yang ;

Cao, Xuetao .

CELL, 2013, 152 (03) :467-478

[4] Modulation of TLR Signaling by Multiple MyD88-Interacting Partners Including Leucine-Rich Repeat Fli-I-Interacting Proteins [J].

Dai, Penggao ;

Jeong, Sun Yong ;

Yu, Yanbao ;

Leng, Taohua ;

Wu, Weidong ;

Xie, Ling ;

Chen, Xian .

JOURNAL OF IMMUNOLOGY, 2009, 182 (06) :3450-3460

[5] The Inflammasome NLRs in Immunity, Inflammation, and Associated Diseases [J].

Davis, Beckley K. ;

Wen, Haitao ;

Ting, Jenny P. -Y. .

ANNUAL REVIEW OF IMMUNOLOGY, VOL 29, 2011, 29 :707-735

[6] Novel proteins interacting with the leucine-rich repeat domain of human flightless-I identified by the yeast two-hybrid system [J].

Fong, KSK ;

de Couet, HG .

GENOMICS, 1999, 58 (02) :146-157

[7] Transcription profiling in human platelets reveals LRRFIP1 as a novel protein regulating platelet function [J].

Goodall, Alison H. ;

Burns, Philippa ;

Salles, Isabelle ;

Macaulay, Iain C. ;

Jones, Chris I. ;

Ardissino, Diego ;

de Bono, Bernard ;

Bray, Sarah L. ;

Deckmyn, Hans ;

Dudbridge, Frank ;

Fitzgerald, Desmond J. ;

Garner, Stephen F. ;

Gusnanto, Arief ;

Koch, Kerstin ;

Langford, Cordelia ;

O'Connor, Marie N. ;

Rice, Catherine M. ;

Stemple, Derek ;

Stephens, Jonathan ;

Trip, Mieke D. ;

Zwaginga, Jaap-Jan ;

Samani, Nilesh J. ;

Watkins, Nicholas A. ;

Maguire, Patricia B. ;

Ouwehand, Willem H. .

BLOOD, 2010, 116 (22) :4646-4656

[8] Type I Interferon Inhibits Interleukin-1 Production and Inflammasome Activation [J].

Guarda, Greta ;

Braun, Marion ;

Staehli, Francesco ;

Tardivel, Aubry ;

Mattmann, Chantal ;

Foerster, Irmgard ;

Farlik, Matthias ;

Decker, Thomas ;

Du Pasquier, Renaud A. ;

Romero, Pedro ;

Tschopp, Juerg .

IMMUNITY, 2011, 34 (02) :213-223

[9] Unambiguous Characterization of Site-specific Phosphorylation of Leucine-rich Repeat Fli-I-interacting Protein 2 (LRRFIP2) in Toll-like Receptor 4 (TLR4)-mediated Signaling [J].

Gunawardena, Harsha P. ;

Huang, Yi ;

Kenjale, Roma ;

Wang, Haiyang ;

Xie, Ling ;

Chen, Xian .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286 (13) :10897-10910

[10] Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3 [J].

Kanneganti, TD ;

Özören, N ;

Body-Malapel, M ;

Amer, A ;

Park, JH ;

Franchi, L ;

Whitfield, J ;

Barchet, W ;

Colonna, M ;

Vandenabeele, P ;

Bertin, J ;

Coyle, A ;

Grant, EP ;

Akira, S ;

Núñez, G .

NATURE, 2006, 440 (7081) :233-236

← 1 2 3 4 →