Activation of human macrophage sodium channels regulates RNA processing to increase expression of the DNA repair protein PPP1R10.

Autor: White CR; Department of Neurology, University of Illinois College of Medicine, Chicago, IL 60612, United States., Dungan M; Department of Neurology, University of Illinois College of Medicine, Chicago, IL 60612, United States., Carrithers MD; Department of Neurology, University of Illinois College of Medicine, Chicago, IL 60612, United States; Program in Neuroscience, University of Illinois College of Medicine, Chicago, IL 60612, United States; Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, United States. Electronic address: mcar1@uic.edu.
Jazyk: angličtina
Zdroj: Immunobiology [Immunobiology] 2019 Jan; Vol. 224 (1), pp. 80-93. Date of Electronic Publication: 2018 Oct 24.
DOI: 10.1016/j.imbio.2018.10.005
Abstrakt: Prior work demonstrated that a splice variant of SCN5A, a voltage-gated sodium channel gene, acts as a cytoplasmic sensor for viral dsRNA in human macrophages. Expression of this channel also polarizes macrophages to an anti-inflammatory phenotype in vitro and in vivo. Here we utilized global expression analysis of splice variants to identify novel channel-dependent signaling mechanisms. Pharmacological activation of voltage-gated sodium channels in human macrophages, but not treatment with cytoplasmic poly I:C, was associated with splicing of a retained intron in transcripts of PPP1R10, a regulator of phosphatase activity and DNA repair. Microarray analysis also demonstrated expression of a novel sodium channel splice variant, human macrophage SCN10A, that contains a similar exon deletion as SCN5A. SCN10A localizes to cytoplasmic and nuclear vesicles in human macrophages. Simultaneous expression of human macrophage SCN5A and SCN10A was required to decrease expression of the retained intron and increase protein expression of PPP1R10. Channel activation also increased protein expression of the splicing factor EFTUD2, and knockdown of EFTUD2 prevented channel dependent splicing of the retained PPP1R10 intron. Knockdown of the SCN5A and SCN10A variants in human macrophages reduced the severity of dsDNA breaks induced by treatment with bleomycin and type 1 interferon. These results suggested that human macrophage SCN5A and SCN10A variants mediate an innate immune signaling pathway that limits DNA damage through increased expression of PPP1R10. The functional significance of this pathway is that it may prevent cytotoxicity during inflammatory responses.
(Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: