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.
Highlights
The success of the vertebrate immune system relies on a remarkable potential to generate highly diverse detection, transduction and effector mechanisms in addition to the ability of individual cells to rapidly adapt and respond to changing environmental conditions [1]
THP-1 cells secrete IL-1b in response to E. coli challenge The sequence of events culminating in IL-1b secretion is complex, but can be summarized in two steps: induction of pro-IL1b and its processing by activated caspase-1
The human monocytic cell line THP-1 has been a preferred in vitro model system to study the mechanisms of IL-1b induction and processing [19]
Summary
The success of the vertebrate immune system relies on a remarkable potential to generate highly diverse detection, transduction and effector mechanisms in addition to the ability of individual cells to rapidly adapt and respond to changing environmental conditions [1]. Transcriptional regulation in the immune system has received the most attention in recent years, but achieving such diversity and flexibility of function requires the operation of additional mechanisms of gene regulation. Two recent landmark reports estimate that 92% to 95% of all human primary transcripts can undergo alternative splicing [8,9]. This process seems to be especially prevalent and functionally significant in the immune and nervous systems [4,10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
