A single domain antibody fragment that recognizes the adaptor ASC defines the role of ASC domains in inflammasome assembly

被引：130

作者：

Schmidt, Florian I. ^{[1
]}

Lu, Alvin ^{[2
,3
]}

Chen, Jeff W. ^{[1
]}

Ruan, Jianbin ^{[2
,3
]}

Tang, Catherine ^{[2
,3
]}

Wu, Hao ^{[2
,3
]}

Ploegh, Hidde L. ^{[1
,4
]}

机构：

[1] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA

[2] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[3] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA

[4] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2016年 / 213卷 / 05期

基金：

瑞士国家科学基金会; 美国国家卫生研究院;

关键词：

CASPASE RECRUITMENT DOMAIN; PROTECTIVE ANTIGEN; ANTHRAX TOXIN; LETHAL FACTOR; CELL-DEATH; PROTEIN; ACTIVATION; EXPRESSION; NANOBODIES; NLRC4;

D O I：

10.1084/jem.20151790

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Myeloid cells assemble inflammasomes in response to infection or cell damage; cytosolic sensors activate pro-caspase-1, indirectly for the most part, via the adaptors ASC and NLRC4. This leads to secretion of proinflammatory cytokines and pyroptosis. To explore complex formation under physiological conditions, we generated an alpaca single domain antibody, VHHASC, which specifically recognizes the CARD of human ASC via its type II interface. VHHASC not only impairs ASC(CARD) interactions in vitro, but also inhibits inflammasome activation in response to NLRP3, AIM2, and NAIP triggers when expressed in living cells, highlighting a role of ASC in all three types of inflammasomes. VHHASC leaves the Pyrin domain of ASC functional and stabilizes a filamentous intermediate of inflammasome activation. Incorporation of VHHASC-EGFP into these structures allowed the visualization of endogenous ASC(PYD) filaments for the first time. These data revealed that cross-linking of ASC(PYD) filaments via ASC(CARD) mediates the assembly of ASC foci.

引用

页码：771 / 790

页数：20

共 54 条

[1] PHENIX: a comprehensive Python']Python-based system for macromolecular structure solution [J].

Adams, Paul D. ;

Afonine, Pavel V. ;

Bunkoczi, Gabor ;

Chen, Vincent B. ;

Davis, Ian W. ;

Echols, Nathaniel ;

Headd, Jeffrey J. ;

Hung, Li-Wei ;

Kapral, Gary J. ;

Grosse-Kunstleve, Ralf W. ;

McCoy, Airlie J. ;

Moriarty, Nigel W. ;

Oeffner, Robert ;

Read, Randy J. ;

Richardson, David C. ;

Richardson, Jane S. ;

Terwilliger, Thomas C. ;

Zwart, Peter H. .

ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2010, 66 :213-221

[2] REMOVAL OF ENDOTOXIN FROM PROTEIN SOLUTIONS BY PHASE-SEPARATION USING TRITON X-114 [J].

AIDA, Y ;

PABST, MJ .

JOURNAL OF IMMUNOLOGICAL METHODS, 1990, 132 (02) :191-195

[3] A SNARE complex mediating fusion of late endosomes defines conserved properties of SNARE structure and function [J].

Antonin, W ;

Holroyd, C ;

Fasshauer, D ;

Pabst, S ;

von Mollard, GF ;

Jahn, R .

EMBO JOURNAL, 2000, 19 (23) :6453-6464

[4]

ARORA N, 1993, J BIOL CHEM, V268, P3334

[5] Intracellular Expression of Camelid Single-Domain Antibodies Specific for Influenza Virus Nucleoprotein Uncovers Distinct Features of Its Nuclear Localization [J].

Ashour, Joseph ;

Schmidt, Florian I. ;

Hanke, Leo ;

Cragnolini, Juanjo ;

Cavallari, Marco ;

Altenburg, Arwen ;

Brewer, Rebeccah ;

Ingram, Jessica ;

Shoemaker, Charles ;

Ploegh, Hidde L. .

JOURNAL OF VIROLOGY, 2015, 89 (05) :2792-2800

[6] High-throughput mapping of a dynamic signaling network in mammalian cells [J].

Barrios-Rodiles, M ;

Brown, KR ;

Ozdamar, B ;

Bose, R ;

Liu, Z ;

Donovan, RS ;

Shinjo, F ;

Liu, YM ;

Dembowy, J ;

Taylor, IW ;

Luga, V ;

Przulj, N ;

Robinson, M ;

Suzuki, H ;

Hayashizaki, Y ;

Jurisica, I ;

Wrana, JL .

SCIENCE, 2005, 307 (5715) :1621-1625

[7] Differential Requirement for Caspase-1 Autoproteolysis in Pathogen-Induced Cell Death and Cytokine Processing [J].

Broz, Petr ;

von Moltke, Jakob ;

Jones, Jonathan W. ;

Vance, Russell E. ;

Monack, Denise M. .

CELL HOST & MICROBE, 2010, 8 (06) :471-483

[8] Redundant roles for inflammasome receptors NLRP3 and NLRC4 in host defense against Salmonella [J].

Broz, Petr ;

Newton, Kim ;

Lamkanfi, Mohamed ;

Mariathasan, Sanjeev ;

Dixit, Vishva M. ;

Monack, Denise M. .

JOURNAL OF EXPERIMENTAL MEDICINE, 2010, 207 (08) :1745-1755

[9] Structural basis for chemokine recognition and activation of a viral G protein-coupled receptor [J].

Burg, John S. ;

Ingram, Jessica R. ;

Venkatakrishnan, A. J. ;

Jude, Kevin M. ;

Dukkipati, Abhiram ;

Feinberg, Evan N. ;

Angelini, Alessandro ;

Waghray, Deepa ;

Dror, Ron O. ;

Ploegh, Hidde L. ;

Garcia, K. Christopher .

SCIENCE, 2015, 347 (6226) :1113-1117

[10] Prion-like Polymerization Underlies Signal Transduction in Antiviral Immune Defense and Inflammasome Activation [J].

Cai, Xin ;

Chen, Jueqi ;

Xu, Hui ;

Liu, Siqi ;

Jiang, Qiu-Xing ;

Halfmann, Randal ;

Chen, Zhijian J. .

CELL, 2014, 156 (06) :1207-1222

← 1 2 3 4 5 6 →