title: An shRNA-based screen of splicing regulators identifies SFRS3 as a negative regulator of IL-1β secretion.
abstract: The generation of diversity and plasticity of transcriptional programs are key components of effective vertebrate immune responses. The role of Alternative Splicing has been recognized, but it is underappreciated and poorly understood as a critical mechanism for the regulation and fine-tuning of physiological immune responses. Here we report the generation of loss-of-function phenotypes for a large collection of genes known or predicted to be involved in the splicing reaction and the identification of 19 novel regulators of IL-1β secretion in response to E. coli challenge of THP-1 cells. Twelve of these genes are required for IL-1β secretion, while seven are negative regulators of this process. Silencing of SFRS3 increased IL-1β secretion due to elevation of IL-1β and caspase-1 mRNA in addition to active caspase-1 levels. This study points to the relevance of splicing in the regulation of auto-inflammatory diseases.
authors: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors: Pedro
authors: P
authors: Moura-Alves
authors: Ana
authors: A
authors: Neves-Costa
authors: Helena
authors: H
authors: Raquel
authors: Teresa Raquel
authors: TR
authors: Pacheco
authors: Bruno
authors: B
authors: D'Almeida
authors: Raquel
authors: R
authors: Rodrigues
authors: Iris
authors: I
authors: Cadima-Couto
authors: Ângelo
authors: Â
authors: Chora
authors: Mariana
authors: M
authors: Oliveira
authors: Margarida
authors: M
authors: Gama-Carvalho
authors: Nir
authors: N
authors: Hacohen
authors: Luis F
authors: LF
authors: Moita
references: Curr Protoc Immunol. 2001 May;Chapter 3:Unit 3.7
references: 18432791
references: Mol Syst Biol. 2010 Jun 8;6:371
references: 20531401
references: Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11218-23
references: 18678901
references: Science. 2005 May 6;308(5723):826-33
references: 15817814
references: Genes Dev. 2010 Apr 1;24(7):625-35
references: 20360381
references: J Exp Med. 1992 Dec 1;176(6):1693-702
references: 1460426
references: Mol Cell. 2009 Jul 10;35(1):1-10
references: 19595711
references: N Engl J Med. 2009 Jun 4;360(23):2467-70
references: 19494224
references: Nature. 2002 Sep 12;419(6903):182-5
references: 12226669
references: Nucleic Acids Res. 2001 May 1;29(9):e45
references: 11328886
references: Cell Microbiol. 2010 Aug;12(8):1046-63
references: 20148899
references: Science. 2002 Dec 13;298(5601):2205-8
references: 12411573
references: Science. 2008 Aug 1;321(5889):686-91
references: 18669861
references: Gene. 2005 Jan 3;344:1-20
references: 15656968
references: Nat Genet. 2008 Dec;40(12):1413-5
references: 18978789
references: Adv Immunol. 2006;89:1-37
references: 16682271
references: J Clin Pathol. 2006 Aug;59(8):855-61
references: 16574722
references: Nat Rev Immunol. 2004 Dec;4(12):931-40
references: 15573128
references: Blood. 2009 Mar 5;113(10):2324-35
references: 19104081
references: Nature. 2006 Mar 9;440(7081):237-41
references: 16407889
references: Hum Genet. 1992 Sep-Oct;90(1-2):41-54
references: 1427786
references: Annu Rev Immunol. 2009;27:229-65
references: 19302040
references: Eur J Haematol. 2008 Jan;80(1):10-9
references: 18173740
references: Biochim Biophys Acta. 2009 Jan;1792(1):14-26
references: 18992329
references: Gene. 2008 Nov 1;423(2):97-107
references: 18718859
references: Proc Natl Acad Sci U S A. 2008 Jun 10;105(23):8067-72
references: 18523012
references: Cell. 1997 Oct 31;91(3):295-8
references: 9363937
references: Nat Immunol. 2009 Mar;10(3):241-7
references: 19221555
references: Nature. 2008 Nov 27;456(7221):470-6
references: 18978772
references: PLoS Pathog. 2010 Feb 26;6(2):e1000661
references: 20195505
references: Cell. 2002 Jul 26;110(2):191-202
references: 12150927
references: Cell. 2006 Mar 24;124(6):1283-98
references: 16564017
references: Genome Res. 2006 Jan;16(1):66-77
references: 16344558
references: Mol Cell. 2002 Aug;10(2):417-26
references: 12191486
references: Nature. 2001 Feb 15;409(6822):860-921
references: 11237011
references: Annu Rev Immunol. 2010;28:367-88
references: 20192808
references: Cell Host Microbe. 2008 Sep 11;4(3):198-208
references: 18779046
references: J Med Chem. 2003 Apr 10;46(8):1318-29
references: 12672232
references: Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):15974-9
references: 15492211
references: Genome Res. 2002 Aug;12(8):1231-45
references: 12176931