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

Null mutations of spliceosome components or cofactors are homozygous lethal in eukaryotes, but viable hypomorphic mutations provide an opportunity to understand the physiological impact of individual splicing proteins. We describe a viable missense allele (F181I) of Rnps1 encoding an essential regul...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2022-05, Vol.119 (18), p.e2200128119-e2200128119
Main Authors: Zhong, Xue, Choi, Jin Huk, Hildebrand, Sara, Ludwig, Sara, Wang, Jianhui, Nair-Gill, Evan, Liao, Tzu-Chieh, Moresco, James J, Liu, Aijie, Quan, Jiexia, Sun, Qihua, Zhang, Duanwu, Zhan, Xiaoming, Choi, Mihwa, Li, Xiaohong, Wang, Junmei, Gallagher, Thomas, Moresco, Eva Marie Y, Beutler, Bruce
Format: Article
Language:English
Subjects:
Alternative splicing
Animals
Apoptosis
Biological Sciences
CD8 antigen
CD8-Positive T-Lymphocytes - metabolism
Cell death
Cofactors
Eukaryotes
Exons
Genetic screening
Hematopoiesis
Hematopoiesis - genetics
Hematopoietic stem cells
Homozygote
Immune system
Introns
Lymphocytes
Lymphocytes T
Mammals - metabolism
Mice
Mutation
Receptors, Tumor Necrosis Factor - metabolism
Ribonucleoproteins - metabolism
Sequence Deletion
Signaling
Spleen
Splicing
Stem cell transplantation
Stem cells
Tumor necrosis factor
Tumor necrosis factor-TNF
Tumor Necrosis Factors - metabolism
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Summary:Null mutations of spliceosome components or cofactors are homozygous lethal in eukaryotes, but viable hypomorphic mutations provide an opportunity to understand the physiological impact of individual splicing proteins. We describe a viable missense allele (F181I) of Rnps1 encoding an essential regulator of splicing and nonsense-mediated decay (NMD), identified in a mouse genetic screen for altered immune cell development. Homozygous mice displayed a stem cell–intrinsic defect in hematopoiesis of all lineages due to excessive apoptosis induced by tumor necrosis factor (TNF)–dependent death signaling. Numerous transcript splice variants containing retained introns and skipped exons were detected at elevated frequencies in Rnps1F181I/F181I splenic CD8+ T cells and hematopoietic stem cells (HSCs), but NMD appeared normal. Strikingly, Tnf knockout rescued all hematopoietic cells to normal or near-normal levels in Rnps1F181I/F181I mice and dramatically reduced intron retention in Rnps1F181I/F181I CD8+ T cells and HSCs. Thus, RNPS1 is necessary for accurate splicing, without which disinhibited TNF signaling triggers hematopoietic cell death.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2200128119