title: Systematic discovery of TLR signaling components delineates viral-sensing circuits.
abstract: Deciphering the signaling networks that underlie normal and disease processes remains a major challenge. Here, we report the discovery of signaling components involved in the Toll-like receptor (TLR) response of immune dendritic cells (DCs), including a previously unkown pathway shared across mammalian antiviral responses. By combining transcriptional profiling, genetic and small-molecule perturbations, and phosphoproteomics, we uncover 35 signaling regulators, including 16 known regulators, involved in TLR signaling. In particular, we find that Polo-like kinases (Plk) 2 and 4 are essential components of antiviral pathways in vitro and in vivo and activate a signaling branch involving a dozen proteins, among which is Tnfaip2, a gene associated with autoimmune diseases but whose role was unknown. Our study illustrates the power of combining systematic measurements and perturbations to elucidate complex signaling circuits and discover potential therapeutic targets.
authors.affiliation: Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chevrier
authors.forename: Philipp
authors.initials: P
authors.lastname: Mertins
authors.forename: Maxim N
authors.initials: MN
authors.lastname: Artyomov
authors.forename: Alex K
authors.initials: AK
authors.lastname: Shalek
authors.forename: Matteo
authors.initials: M
authors.lastname: Iannacone
authors.forename: Mark F
authors.initials: MF
authors.lastname: Ciaccio
authors.forename: Irit
authors.initials: I
authors.lastname: Gat-Viks
authors.forename: Elena
authors.initials: E
authors.lastname: Tonti
authors.forename: Marciela M
authors.initials: MM
authors.lastname: DeGrace
authors.forename: Karl R
authors.initials: KR
authors.lastname: Clauser
authors.forename: Manuel
authors.initials: M
authors.lastname: Garber
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Eisenhaure
authors.forename: Nir
authors.initials: N
authors.lastname: Yosef
authors.forename: Jacob
authors.initials: J
authors.lastname: Robinson
authors.forename: Amy
authors.initials: A
authors.lastname: Sutton
authors.forename: Mette S
authors.initials: MS
authors.lastname: Andersen
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.forename: Ulrich
authors.initials: U
authors.lastname: von Andrian
authors.forename: Richard B
authors.initials: RB
authors.lastname: Jones
authors.forename: Hongkun
authors.initials: H
authors.lastname: Park
authors.forename: Steven A
authors.initials: SA
authors.lastname: Carr
authors.forename: Aviv
authors.initials: A
authors.lastname: Regev
authors.forename: Ido
authors.initials: I
authors.lastname: Amit
authors.forename: Nir
authors.initials: N
authors.lastname: Hacohen
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D007372:Interferons / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism*; D014780:Viruses
chemical_list: C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D051193:Toll-Like Receptors; D007372:Interferons; D017346:Protein Serine-Threonine Kinases
references.citation: J Proteome Res. 2010 May 7;9(5):2539-49
references.pmid: 20222745
references.citation: Nat Genet. 2007 Apr;39(4):503-12
references.pmid: 17322878
references.citation: Immunity. 2010 Apr 23;32(4):518-30
references.pmid: 20362473
references.citation: Oncogene. 2005 Jan 10;24(2):292-8
references.pmid: 15640845
references.citation: Mol Syst Biol. 2010 Jun 8;6:371
references.pmid: 20531401
references.citation: Nature. 2000 Nov 16;408(6810):313-9
references.pmid: 11099031
references.citation: Immunity. 2006 Sep;25(3):383-92
references.pmid: 16979570
references.citation: Mol Biol Cell. 2010 Jul 15;21(14):2500-13
references.pmid: 20484576
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):1870-5
references.pmid: 20080678
references.citation: Nat Chem Biol. 2011 Jan;7(1):25-33
references.pmid: 21076398
references.citation: Nature. 2010 Jun 24;465(7301):1079-83
references.pmid: 20577213
references.citation: J Clin Oncol. 2008 Dec 1;26(34):5511-7
references.pmid: 18955456
references.citation: Nat Rev Drug Discov. 2010 Apr;9(4):293-307
references.pmid: 20380038
references.citation: Cell Microbiol. 2010 Jun;12(6):831-43
references.pmid: 20088952
references.citation: J Exp Med. 2003 Mar 17;197(6):777-88
references.pmid: 12642605
references.citation: Cell. 2010 Mar 19;140(6):805-20
references.pmid: 20303872
references.citation: J Exp Med. 2007 Apr 16;204(4):853-63
references.pmid: 17420270
references.citation: Nat Protoc. 2008;3(10):1630-8
references.pmid: 18833199
references.citation: Nat Rev Drug Discov. 2010 Aug;9(8):643-60
references.pmid: 20671765
references.citation: Immunogenetics. 1999 Feb;49(2):79-85
references.pmid: 9887344
references.citation: J Biol Chem. 2009 Aug 14;284(33):21797-21809
references.pmid: 19546225
references.citation: Nat Biotechnol. 2008 Dec;26(12):1367-72
references.pmid: 19029910
references.citation: Immunity. 2010 Mar 26;32(3):305-15
references.pmid: 20346772
references.citation: Annu Rev Immunol. 2011;29:163-83
references.pmid: 21219184
references.citation: EMBO J. 2010 Jul 21;29(14):2395-406
references.pmid: 20531387
references.citation: Science. 2009 Oct 9;326(5950):257-63
references.pmid: 19729616
references.citation: Nature. 2002 Apr 18;416(6882):744-9
references.pmid: 11961557
references.citation: Immunity. 1999 Dec;11(6):721-31
references.pmid: 10626894
references.citation: Cell. 2007 Dec 14;131(6):1124-36
references.pmid: 18083102
references.citation: Nature. 2009 Nov 5;462(7269):108-12
references.pmid: 19847166
references.citation: J Immunol. 2009 Dec 15;183(12):7975-83
references.pmid: 19923465
references.citation: Nature. 2007 Jun 7;447(7145):661-78
references.pmid: 17554300
references.citation: Mol Cell Proteomics. 2002 May;1(5):376-86
references.pmid: 12118079
references.citation: Immunity. 2002 Sep;17(3):251-63
references.pmid: 12354379
references.citation: J Biol Chem. 2008 Feb 29;283(9):5719-27
references.pmid: 18165234
references.citation: Nat Immunol. 2009 Apr;10(4):327-31
references.pmid: 19295628
references.citation: Immunol Rev. 2008 Jun;223:271-83
references.pmid: 18613842
references.citation: J Immunol. 2006 Nov 1;177(9):5785-9
references.pmid: 17056502
references.citation: Cell Cycle. 2008 Nov 15;7(22):3548-55
references.pmid: 19001868
references.citation: Cell. 2006 Oct 6;127(1):157-70
references.pmid: 17018283
references.citation: Nat Rev Mol Cell Biol. 2009 Apr;10(4):265-75
references.pmid: 19305416
references.citation: Nat Immunol. 2009 Sep;10(9):965-72
references.pmid: 19668221
references.citation: Nat Methods. 2010 Feb;7(2):148-55
references.pmid: 20101245
references.citation: Genes Dev. 1991 May;5(5):868-79
references.pmid: 1851123
references.citation: Cell Commun Signal. 2009 May 10;7:13
references.pmid: 19426560