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

doi:10.1073/pnas.2200128119

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 journal › Article › peer-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 language	English (US)
Pages (from-to)	e2200128119
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	119
Issue number	18
DOIs	https://doi.org/10.1073/pnas.2200128119
State	Published - May 3 2022

Keywords

apoptosis
hematopoiesis
splicing
TNF

ASJC Scopus subject areas

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10.1073/pnas.2200128119

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Zhong, X., Choi, J. H., Hildebrand, S., Ludwig, S., Wang, J., Nair-Gill, E., Liao, T. C., Moresco, J. J., Liu, A., Quan, J., Sun, Q., Zhang Ph.D., D-W., Zhan, X., Choi, M., Li, X., Wang, J., Gallagher, T., Moresco, E. M. Y., & Beutler, B. (2022). RNPS1 inhibits excessive tumor necrosis factor/tumor necrosis factor receptor signaling to support hematopoiesis in mice. Proceedings of the National Academy of Sciences of the United States of America, 119(18), e2200128119. https://doi.org/10.1073/pnas.2200128119

RNPS1 inhibits excessive tumor necrosis factor/tumor necrosis factor receptor signaling to support hematopoiesis in mice. / 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 Ph.D., Duan-Wu; Zhan, Xiaoming ; Choi, Mihwa ; Li, Xiaohong; Wang, Junmei; Gallagher, Thomas; Moresco, Eva Marie Y.; Beutler, Bruce.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 119, No. 18, 03.05.2022, p. e2200128119.

Research output: Contribution to journal › Article › peer-review

Zhong, X, Choi, JH, Hildebrand, S, Ludwig, S, Wang, J, Nair-Gill, E, Liao, TC, Moresco, JJ, Liu, A, Quan, J, Sun, Q, Zhang Ph.D., D-W, Zhan, X , Choi, M , Li, X, Wang, J, Gallagher, T, Moresco, EMY & Beutler, B 2022, 'RNPS1 inhibits excessive tumor necrosis factor/tumor necrosis factor receptor signaling to support hematopoiesis in mice', Proceedings of the National Academy of Sciences of the United States of America, vol. 119, no. 18, pp. e2200128119. https://doi.org/10.1073/pnas.2200128119

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 Ph.D., Duan-Wu ; Zhan, Xiaoming ; Choi, Mihwa ; Li, Xiaohong ; Wang, Junmei ; Gallagher, Thomas ; Moresco, Eva Marie Y. ; Beutler, Bruce. / RNPS1 inhibits excessive tumor necrosis factor/tumor necrosis factor receptor signaling to support hematopoiesis in mice. In: Proceedings of the National Academy of Sciences of the United States of America. 2022 ; Vol. 119, No. 18. pp. e2200128119.

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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.",

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AU - Zhong, Xue

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AU - Ludwig, Sara

AU - Wang, Jianhui

AU - Nair-Gill, Evan

AU - Liao, Tzu Chieh

AU - Moresco, James J.

AU - Liu, Aijie

AU - Quan, Jiexia

AU - Sun, Qihua

AU - Zhang Ph.D., Duan-Wu

AU - Zhan, Xiaoming

AU - Choi, Mihwa

AU - Li, Xiaohong

AU - Wang, Junmei

AU - Gallagher, Thomas

AU - Moresco, Eva Marie Y.

AU - Beutler, Bruce

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AB - 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.

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

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