Article thumbnail

An shRNA-Based Screen of Splicing Regulators Identifies SFRS3 as a Negative Regulator of IL-1β Secretion

By Pedro Moura-Alves, Ana Neves-Costa, Helena Raquel, Teresa Raquel Pacheco, Bruno D'Almeida, Raquel Rodrigues, Iris Cadima-Couto, Ângelo Chora, Mariana Oliveira, Margarida Gama-Carvalho, Nir Hacohen and Luis F. Moita


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

Topics: Research Article
Publisher: Public Library of Science
OAI identifier:
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles


  1. (2008). A highthroughput screening strategy identifies cardiotonic steroids as alternative splicing modulators.
  2. (2006). A lentiviral RNAi library for human and mouse genes applied to an arrayed viral high-content screen.
  3. (2001). A new mathematical model for relative quantification in realtime RT-PCR.
  4. (2008). Alternative isoform regulation in human tissue transcriptomes.
  5. (2009). Alternative splicing and disease.
  6. (2006). Alternative splicing factor ASF/SF2 is down regulated in inflamed muscle.
  7. (2008). Alternative splicing in the NF-kappaB signaling pathway.
  8. (2008). ATP is released by monocytes stimulated with pathogen-sensing receptor ligands and induces IL-1beta and IL-18 secretion in an autocrine way.
  9. (2002). Comprehensive proteomic analysis of the human spliceosome.
  10. (2004). Consequences of regulated pre-mRNA splicing in the immune system.
  11. (2008). Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing.
  12. (2009). Differential requirement for the activation of the inflammasome for processing and release of IL-1beta in monocytes and macrophages.
  13. Fulga TA Understanding neuronal connectivity through the post-transcriptional toolkit.
  14. (2005). Function of alternative splicing.
  15. (2005). Functional genomic analysis of the Wnt-wingless signaling pathway.
  16. (1992). Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor.
  17. (2006). Gout-associated uric acid crystals activate the NALP3 inflammasome.
  18. (2004). Identification of alternative splicing regulators by RNA interference in Drosophila.
  19. IL-1beta processing in host defense: beyond the inflammasomes.
  20. (2001). Initial sequencing and analysis of the human genome.
  21. (1997). Innate immunity: the virtues of a nonclonal system of recognition.
  22. (2009). Interleukin-1beta and the autoinflammatory diseases.
  23. (2008). Intracellular HMGB1 transactivates the human IL1B gene promoter through association with an Ets transcription factor PU.1.
  24. (2002). IRAK-M is a negative regulator of Toll-like receptor signaling.
  25. (2001). Isolation of dendritic cells.
  26. (2002). Large-scale proteomic analysis of the human spliceosome.
  27. (2006). Posttranscriptional mechanisms regulating the inflammatory response.
  28. (2008). Regulation of CD45 alternative splicing by heterogeneous ribonucleoprotein, hnRNPLL.
  29. (2011). SFRS3 Is a Negative Regulator of IL-1b Secretion
  30. (2002). Small nuclear ribonucleoprotein remodeling during catalytic activation of the spliceosome.
  31. (2009). SR proteins in vertical integration of gene expression from transcription to RNA processing to translation.
  32. (2003). Synthesis and biological activity of N-arylpiperazine-modified analogues of KN-62, a potent antagonist of the purinergic P2X7 receptor.
  33. (2006). Systematic genomewide annotation of spliceosomal proteins reveals differential gene family expansion.
  34. (2008). The caspase-1 inflammasome: a pilot of innate immune responses.
  35. (2009). The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis.
  36. (2002). The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proILbeta.
  37. (2009). The inflammasomes: guardians of the body.
  38. (1992). The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences.
  39. The phosphoproteome of toll-like receptor-activated macrophages.