Open AccessRNPS1 inhibits excessive tumor necrosis factor/tumor necrosis factor receptor signaling to support hematopoiesis in mice
Author(s) -
Xue Zhong,
Jin Huk Choi,
Sara Hildebrand,
Sara Ludwig,
Jianhui Wang,
Evan Nair-Gill,
Tzu-Chieh Liao,
James J. Moresco,
Aijie Liu,
Jia Quan,
Qian Sun,
Duanwu Zhang,
Xiaoming Zhan,
Mihwa Choi,
Xiaohong Li,
Junmei Wang,
T. F. Gallagher,
Eva Marie Y. Moresco,
Bruce Beutler
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2200128119
Subject(s) - biology , haematopoiesis , rna splicing , tumor necrosis factor alpha , spliceosome , hematopoietic stem cell , stem cell , microbiology and biotechnology , intron , exon , splicing factor , cancer research , genetics , alternative splicing , immunology , rna , gene
Significance Messenger 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.