A unique death pathway keeps RIPK1 D325A mutant mice in check at embryonic day 10.5.
A unique death pathway keeps RIPK1 D325A mutant mice in check at embryonic day 10.5.
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独特的死亡途径使 RIPK1 D325A 突变小鼠在胚胎第 10.5 天受到控制
DOI：
10.1371/journal.pbio.3001304
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发表时间：
2021-08
期刊：
影响因子：
9.8
通讯作者：
Han J
中科院分区：
文献类型：
--
作者：
Zhang Y;Huang K;Zhang Y;Han T;Li L;Ruan C;Sun YH;Shi W;Han W;Wu SQ;Song J;Liu J;Han J
肿瘤坏死因子受体-1 （TNFR1）信号除了在炎症中具有多效性外，还在胚胎发生中发挥作用，因为其下游分子种类的缺乏导致小鼠胚胎死亡。Caspase-8不可切割受体相互作用丝氨酸/苏氨酸激酶1 （RIPK1）突变在人类中自然发生，而小鼠RIPK1中相应的D325A突变可导致妊娠早期死亡。众所周知，Ripk1D325A/D325A胚胎的死亡和Casp8 - / -小鼠的死亡都是由TNFR1启动的，但它们分别是由细胞凋亡和坏死凋亡介导的。在这里，我们发现Ripk1D325A/D325A胚胎中的缺陷发生在胚胎第10.5天（E10.5），比Casp8基因敲除引起的缺陷早。通过分析一系列基因突变小鼠，我们阐明了导致Ripk1D325A/D325A胚胎致死的机制，并将其与Casp8缺失介导的致死机制进行了比较。我们发现Ripk1D325A/D325A胚胎的凋亡需要RIPK3的支架功能和酶活性caspase-8。出乎意料的是，caspase-1和caspase-11位于活化的caspase-8的下游，Casp1和Casp11的同时缺失将E10.5的致死时间推迟到胚胎13.5天（E13.5）。此外，caspase-3是Ripk1D325A/D325A小鼠E10.5期凋亡的刽子手，因为它的缺失将Ripk1D325A/D325A小鼠的寿命延长至胚胎期11.5天（E11.5）。因此，TNFR1的意外死亡途径控制着RIPK1 D325A突变诱导的E10.5的致死率。
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.
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影响因子：
16.6
作者：
Kang, Seokwon;Fernandes-Alnemri, Teresa;Rogers, Corey;Mayes, Lindsey;Wang, Ying;Dillon, Christopher;Roback, Linda;Kaiser, William;Oberst, Andrew;Sagara, Junji;Fitzgerald, Katherine A.;Green, Douglas R.;Zhang, Jianke;Mocarski, Edward S.;Alnemri, Emad S.
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Alnemri, Emad S.
影响因子：
24.5
作者：
Južnić L;Peuker K;Strigli A;Brosch M;Herrmann A;Häsler R;Koch M;Matthiesen L;Zeissig Y;Löscher BS;Nuber A;Schotta G;Neumeister V;Chavakis T;Kurth T;Lesche M;Dahl A;von Mässenhausen A;Linkermann A;Schreiber S;Aden K;Rosenstiel PC;Franke A;Hampe J;Zeissig S
通讯作者：
Zeissig S
影响因子：
11.4
作者：
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通讯作者：
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影响因子：
32.4
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通讯作者：
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影响因子：
32.4
作者：
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通讯作者：
Strasser, Andreas