RNPS1 inhibits excessive tumor necrosis factor/tumor necrosis factor receptor signaling to support hematopoiesis in mice

Xue Zhong, Jin Huk Choi, Sara Hildebrand, Sara Ludwig, Jianhui Wang, Evan Nair-Gill, Tzu Chieh Liao, James J. Moresco, Aijie Liu, Jiexia Quan, Qihua Sun, Duan-Wu Zhang Ph.D., Xiaoming Zhan, Mihwa Choi, Xiaohong Li, Junmei Wang, Thomas Gallagher, Eva Marie Y. Moresco, Bruce Beutler

Research output: Contribution to journalArticlepeer-review

Abstract

SignificanceMessenger RNA (mRNA) splicing is fundamental to protein expression in mammals. Homozygous deletion of single protein components of the splicing machinery or its regulatory factors is embryonic lethal. However, through forward genetic screening in mice, we identified a viable hypomorphic missense mutation of the splicing regulator RNPS1. Homozygous mutant mice displayed altered immune cell development due to excessive tumor necrosis factor (TNF)-dependent immune cell apoptosis. Splicing was impaired in CD8+ T cells and hematopoietic stem cells from RNPS1 mutant mice. TNF knockout rescued hematopoiesis and dramatically reduced splicing defects in RNPS1 hematopoietic cells, demonstrating a surprising link between elevated TNF and defects in splicing caused by RNPS1 deficiency.

Original languageEnglish (US)
Pages (from-to)e2200128119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number18
DOIs
StatePublished - May 3 2022

Keywords

  • apoptosis
  • hematopoiesis
  • splicing
  • TNF

ASJC Scopus subject areas

  • General

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