Processing of interleukin RNAs must be tightly controlled during the immune response. Here we report that a subnuclear body called the interleukin-6 and -10 splicing activating compartment (InSAC) is a nuclear site of cytokine RNA production and stability. Tat-activating regulatory DNA-binding protein-43 (TDP-43) acts as an InSAC scaffold that selectively associates with IL-6 and IL-10 RNAs in a sequence-specific manner. TDP-43 also recruits key spliceosomal components from Cajal bodies. LPS induces posttranslational modifications of TDP-43; in particular, TDP-43 ubiquitination provides a driving force for InSAC formation. As a consequence, in vivo depletion of TDP-43 leads to a dramatic reduction in the RNA processing and the protein levels of IL-6 in serum. Collectively, our findings highlight the importance of TDP-43-mediated InSAC biogenesis in immune regulation.
Bibliographical noteFunding Information:
We thank Dr Philip C. Wong (Departments of Pathology, Neuroscience and Neurology, The Johns Hopkins University School of Medicine, Baltimore) for critical reading of the manuscript, and Dr Alxander Hoffmann (University of San Diego, USA) for NF-kB-deficient MEF cells. This study was supported by grants from Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010-0009203 and 2011-0015372), from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (1220060), and from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI14C2542). S.L. and J.-H. Y. were supported by the Yonsei University Research Fund of 2014 (2014-12-0135) and by the NIA-IRP, NIH, respectively. S.L., S.K., T.A.L., E.L. and A.P. were supported by Brain Korea (BK21) PLUS Program.
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All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)