A unique death pathway keeps RIPK1 D325A mutant mice in check at embryonic day 10.5.

Tumor necrosis factor receptor-1 (TNFR1) signaling, apart from its pleiotropic functions in inflammation, plays a role in embryogenesis as deficiency of varieties of its downstream molecules leads to embryonic lethality in mice. Caspase-8 noncleavable receptor interacting serine/threonine kinase 1 (...

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Autores principales:	Yingying Zhang, Kai Huang, Yuxia Zhang, Tao Han, Lang Li, Chenchen Ruan, Ye-Hsuan Sun, Wenke Shi, Wei Han, Su-Qin Wu, Jing Song, Jun Liu, Jiahuai Han
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/62afad1c809e4f7c850606395f0ca928
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spelling	oai:doaj.org-article:62afad1c809e4f7c850606395f0ca9282021-12-02T19:54:38ZA unique death pathway keeps RIPK1 D325A mutant mice in check at embryonic day 10.5.1544-91731545-788510.1371/journal.pbio.3001304https://doaj.org/article/62afad1c809e4f7c850606395f0ca9282021-08-01T00:00:00Zhttps://doi.org/10.1371/journal.pbio.3001304https://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Tumor necrosis factor receptor-1 (TNFR1) signaling, apart from its pleiotropic functions in inflammation, plays a role in embryogenesis as deficiency of varieties of its downstream molecules leads to embryonic lethality in mice. Caspase-8 noncleavable receptor interacting serine/threonine kinase 1 (RIPK1) mutations occur naturally in humans, and the corresponding D325A mutation in murine RIPK1 leads to death at early midgestation. It is known that both the demise of Ripk1D325A/D325A embryos and the death of Casp8-/- mice are initiated by TNFR1, but they are mediated by apoptosis and necroptosis, respectively. Here, we show that the defects in Ripk1D325A/D325A embryos occur at embryonic day 10.5 (E10.5), earlier than that caused by Casp8 knockout. By analyzing a series of genetically mutated mice, we elucidated a mechanism that leads to the lethality of Ripk1D325A/D325A embryos and compared it with that underlies Casp8 deletion-mediated lethality. We revealed that the apoptosis in Ripk1D325A/D325A embryos requires a scaffold function of RIPK3 and enzymatically active caspase-8. Unexpectedly, caspase-1 and caspase-11 are downstream of activated caspase-8, and concurrent depletion of Casp1 and Casp11 postpones the E10.5 lethality to embryonic day 13.5 (E13.5). Moreover, caspase-3 is an executioner of apoptosis at E10.5 in Ripk1D325A/D325A mice as its deletion extends life of Ripk1D325A/D325A mice to embryonic day 11.5 (E11.5). Hence, an unexpected death pathway of TNFR1 controls RIPK1 D325A mutation-induced lethality at E10.5.Yingying ZhangKai HuangYuxia ZhangTao HanLang LiChenchen RuanYe-Hsuan SunWenke ShiWei HanSu-Qin WuJing SongJun LiuJiahuai HanPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 19, Iss 8, p e3001304 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Yingying Zhang Kai Huang Yuxia Zhang Tao Han Lang Li Chenchen Ruan Ye-Hsuan Sun Wenke Shi Wei Han Su-Qin Wu Jing Song Jun Liu Jiahuai Han A unique death pathway keeps RIPK1 D325A mutant mice in check at embryonic day 10.5.
description	Tumor necrosis factor receptor-1 (TNFR1) signaling, apart from its pleiotropic functions in inflammation, plays a role in embryogenesis as deficiency of varieties of its downstream molecules leads to embryonic lethality in mice. Caspase-8 noncleavable receptor interacting serine/threonine kinase 1 (RIPK1) mutations occur naturally in humans, and the corresponding D325A mutation in murine RIPK1 leads to death at early midgestation. It is known that both the demise of Ripk1D325A/D325A embryos and the death of Casp8-/- mice are initiated by TNFR1, but they are mediated by apoptosis and necroptosis, respectively. Here, we show that the defects in Ripk1D325A/D325A embryos occur at embryonic day 10.5 (E10.5), earlier than that caused by Casp8 knockout. By analyzing a series of genetically mutated mice, we elucidated a mechanism that leads to the lethality of Ripk1D325A/D325A embryos and compared it with that underlies Casp8 deletion-mediated lethality. We revealed that the apoptosis in Ripk1D325A/D325A embryos requires a scaffold function of RIPK3 and enzymatically active caspase-8. Unexpectedly, caspase-1 and caspase-11 are downstream of activated caspase-8, and concurrent depletion of Casp1 and Casp11 postpones the E10.5 lethality to embryonic day 13.5 (E13.5). Moreover, caspase-3 is an executioner of apoptosis at E10.5 in Ripk1D325A/D325A mice as its deletion extends life of Ripk1D325A/D325A mice to embryonic day 11.5 (E11.5). Hence, an unexpected death pathway of TNFR1 controls RIPK1 D325A mutation-induced lethality at E10.5.
format	article
author	Yingying Zhang Kai Huang Yuxia Zhang Tao Han Lang Li Chenchen Ruan Ye-Hsuan Sun Wenke Shi Wei Han Su-Qin Wu Jing Song Jun Liu Jiahuai Han
author_facet	Yingying Zhang Kai Huang Yuxia Zhang Tao Han Lang Li Chenchen Ruan Ye-Hsuan Sun Wenke Shi Wei Han Su-Qin Wu Jing Song Jun Liu Jiahuai Han
author_sort	Yingying Zhang
title	A unique death pathway keeps RIPK1 D325A mutant mice in check at embryonic day 10.5.
title_short	A unique death pathway keeps RIPK1 D325A mutant mice in check at embryonic day 10.5.
title_full	A unique death pathway keeps RIPK1 D325A mutant mice in check at embryonic day 10.5.
title_fullStr	A unique death pathway keeps RIPK1 D325A mutant mice in check at embryonic day 10.5.
title_full_unstemmed	A unique death pathway keeps RIPK1 D325A mutant mice in check at embryonic day 10.5.
title_sort	unique death pathway keeps ripk1 d325a mutant mice in check at embryonic day 10.5.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/62afad1c809e4f7c850606395f0ca928
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A unique death pathway keeps RIPK1 D325A mutant mice in check at embryonic day 10.5.

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