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RIP1 kinase activity-dependent roles in embryonic development of Fadd-deficient mice.

ABSTRACT: RIP1 is an essential regulator of TNF-induced signaling complexes mediating NF-?B activation, apoptosis and necroptosis. Loss of Rip1 rescues the embryonic lethality of Fadd or Caspase-8-deficient mice, even though the double knockout mice die shortly after birth like Rip1-deficient mice. Recent studies demonstrated that mice expressing RIP1 kinase-dead mutants developed normally and resisted necroptotic stimuli in vitro and in vivo. However, the impact of RIP1 kinase activity on Fadd^-/- embryonic development remains unknown. Here, we engineered two RIP1 kinase inactive mutant mouse lines, a Rip1^K45A/K45A mouse line as previously reported and a novel Rip1^?/? mouse line with an altered P-loop in the kinase domain. While RIP1^K45A could not rescue the embryonic lethality of Fadd-deficient mice at E11.5, RIP1^? rescued lethality of Fadd^-/- mice at E11.5 and Fadd^-/-Rip1^?/? mice eventually died at E16.5 due to excessive death of fetal liver cells and unregulated inflammation. Under necropotosis-inducing conditions, comparing to Rip1^K45A/K45A cells, Rip1^?/?cells displayed reduced phosphorylation and oligomerization of RIP3 and MLKL, which lead to increased cell viability. Thus, our study provides genetic evidence that different kinase inactive mutations have distinct impacts on the embryogenesis of Fadd-deficient mice, which might attribute to their extents of protection on necroptosis signaling.

SUBMITTER: Liu Y

PROVIDER: S-EPMC5520462 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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RIP1 kinase activity-dependent roles in embryonic development of Fadd-deficient mice.

Liu Yongbo Y Fan Cunxian C Zhang Yifan Y Yu Xianjun X Wu Xiaoxia X Zhang Xixi X Zhao Qun Q Zhang Haiwei H Xie Qun Q Li Ming M Li Xiaoming X Ding Qiurong Q Ying Hao H Li Dali D Zhang Haibing H

Cell death and differentiation 20170602 8

RIP1 is an essential regulator of TNF-induced signaling complexes mediating NF-κB activation, apoptosis and necroptosis. Loss of Rip1 rescues the embryonic lethality of Fadd or Caspase-8-deficient mice, even though the double knockout mice die shortly after birth like Rip1-deficient mice. Recent studies demonstrated that mice expressing RIP1 kinase-dead mutants developed normally and resisted necroptotic stimuli in vitro and in vivo. However, the impact of RIP1 kinase activity on Fadd<sup>-/-</s ...[more]

PMID: 28574501

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Project description:Hepatoma-derived growth factor (HDGF) related protein 2 (HRP2) and lens epithelium-derived growth factor (LEDGF)/p75 are closely related members of the HRP2 protein family. LEDGF/p75 has been implicated in numerous human pathologies including cancer, autoimmunity, and infectious disease. Knockout of the Psip1 gene, which encodes for LEDGF/p75 and the shorter LEDGF/p52 isoform, was previously shown to cause perinatal lethality in mice. The function of HRP2 was by contrast largely unknown. To learn about the role of HRP2 in development, we knocked out the Hdgfrp2 gene, which encodes for HRP2, in both normal and Psip1 knockout mice. Hdgfrp2 knockout mice developed normally and were fertile. By contrast, the double deficient mice died at approximate embryonic day (E) 13.5. Histological examination revealed ventricular septal defect (VSD) associated with E14.5 double knockout embryos. To investigate the underlying molecular mechanism(s), RNA recovered from ventricular tissue was subjected to RNA-sequencing on the Illumina platform. Bioinformatic analysis revealed several genes and biological pathways that were significantly deregulated by the Psip1 knockout and/or Psip1/Hdgfrp2 double knockout. Among the dozen genes known to encode for LEDGF/p75 binding factors, only the expression of Nova1, which encodes an RNA splicing factor, was significantly deregulated by the knockouts. However the expression of other RNA splicing factors, including the LEDGF/p52-interacting protein ASF/SF2, was not significantly altered, indicating that deregulation of global RNA splicing was not a driving factor in the pathology of the VSD. Tumor growth factor (Tgf) β-signaling, which plays a key role in cardiac morphogenesis during development, was the only pathway significantly deregulated by the double knockout as compared to control and Psip1 knockout samples. We accordingly speculate that deregulated Tgf-β signaling was a contributing factor to the VSD and prenatal lethality of Psip1/Hdgfrp2 double-deficient mice.

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RIP1 kinase activity-dependent roles in embryonic development of Fadd-deficient mice.

Publications

RIP1 kinase activity-dependent roles in embryonic development of Fadd-deficient mice.

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