A novel function of RIP1 in postnatal development and immune homeostasis by protecting against RIP3-dependent necroptosis and FADD-mediated apoptosis

Frontiers in Cell and Developmental Biology
John P DowlingJianke Zhang

Abstract

RIP1 is an adaptor kinase originally identified as being able to associate with TNFR1 and Fas, and is later shown to be involved in signaling induced by TLRs. Major signaling pathways regulated by RIP1 include necroptosis, apoptosis, and pro-survival/inflammation NF-κB activation. Previous studies show that RIP1 deficiency has no effect on mouse embryogenesis, but blocks postnatal development. This phenotype could not readily be explained, since mice lacking TNFR1, Fas, or TLRs show no apparent developmental defect. Certain types of RIP1-deficient cells are hypersensitive to TNF-induced apoptosis. However, in our previous study, deletion of the apoptotic adaptor protein, FADD, provides marginal improvement of postnatal development of rip1 (-/-) mice. Remarkably, the current data shows that haploid insufficiency of RIP3, a known mediator of necroptosis, allowed survival of rip1 (-/-) fadd (-/-) mice beyond weaning age, although the resulting rip1(-/-)fadd(-/-) rip3(+/-) mice were significant smaller in size and weight. Moreover, complete absence of RIP3 further improved postnatal development of the resulting rip1 (-/-) fadd (-/-) rip3 (-/-) mice, which display normal size and weight. In such triple knockout (TKO) mice, lymphocyt...Continue Reading

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Citations

Apr 7, 2016·Cellular and Molecular Life Sciences : CMLS·Kenta Moriwaki, Francis Ka-Ming Chan
Jun 19, 2015·Nature Immunology·John SilkeMotti Gerlic
Sep 30, 2016·Cell Death & Disease·John P DowlingJianke Zhang
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Feb 12, 2019·Nature Communications·John P DowlingJianke Zhang
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Jan 13, 2021·Neural Regeneration Research·Wei-Tao YanKun Xiong
Jun 25, 2021·Frontiers in Immunology·Jiahui ZhangQing Zhou

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Methods Mentioned

BETA
ubiquitination
dissection
flow cytometry
FACS

Software Mentioned

Prism
CellTrace
FlowJo
Graphpad
TreeStar

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

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