Cited by 1,057Cell death mechanisms and regulationNF-κB Signaling PathwaysInflammasome and immune disorders

RIP3 mediates the embryonic lethality of caspase-8-deficient mice

Open access
Kaiser, William J., Upton, Jason W., Long, Alyssa B., Livingston-Rosanoff, Devon, Daley-Bauer, Lisa P., Hakem, Razqallah, Caspary, Tamara, Mocarski, Edward S.·2011·Nature

Abstract

Apoptosis and necroptosis are complementary pathways controlled by common signalling adaptors, kinases and proteases; among these, caspase-8 (Casp8) is critical for death receptor-induced apoptosis. This caspase has also been implicated in non-apoptotic pathways that regulate Fas-associated via death domain (FADD)-dependent signalling and other less defined biological processes as diverse as innate immune signalling and myeloid or lymphoid differentiation patterns. Casp8 suppresses RIP3-RIP1 (also known as RIPK3-RIPK1) kinase complex-dependent necroptosis that follows death receptor activation as well as a RIP3-dependent, RIP1-independent necrotic pathway that has emerged as a host defence mechanism against murine cytomegalovirus. Disruption of Casp8 expression leads to embryonic lethality in mice between embryonic days 10.5 and 11.5 (ref. 7). Thus, Casp8 may naturally hold alternative RIP3-dependent death pathways in check in addition to promoting apoptosis. We find that RIP3 is responsible for the mid-gestational death of Casp8-deficient embryos. Remarkably, Casp8(-/-)Rip3(-/-) double mutant mice are viable and mature into fertile adults with a full immune complement of myeloid and lymphoid cell types. These mice seem immunocompetent but develop lymphadenopathy by four months of age marked by accumulation of abnormal T cells in the periphery, a phenotype reminiscent of mice with Fas-deficiency (lpr/lpr; also known as Fas). Thus, Casp8 contributes to homeostatic control in the adult immune system; however, RIP3 and Casp8 are together completely dispensable for mammalian development.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/nature09857

Cites

30 of 30 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Assembly of necrosome upon TNFR1 stimulation impinges on two conditions: pharmacological or genetic CASP8 inactivation, and RIPK1 deubiquitination-dependent phosphorylation (at least in some settings), which can be favored by SMAC mimetics.

    “In addition, the assembly of the necrosome upon TNFR1 stimulation impinges on two conditions: (1) pharmacological or genetic CASP8 inactivation [478, 479], and (2) RIPK1 deubiquitination-dependent phosphorylation (at least in some settings), which can be favored by exogenously provided SMAC mimetics, ensuring the release of RIPK1 from complex I (see above) [334, 335, 480, 481].”

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

1 of the 31 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Authors
Kaiser, W. J., Upton, J. W., Long, A. B., Livingston-Rosanoff, D., Daley-Bauer, L. P., Hakem, R., Caspary, T., & Mocarski, E. S.
Affiliations
  • Emory University (US)
  • University Health Network (CA)
Corresponding author
Kaiser, William J.
Venue
Nature
Published
2011-03
Volume
471
Issue
7338
Pages
368-372
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
OpenAlex
W2042577315
Cited by
1,057
References
31
Citations by year
2026: 37 · 2025: 60 · 2024: 56 · 2023: 51 · 2022: 66 · 2021: 61 · 2020: 70 · 2019: 55 · 2018: 68 · 2017: 59 · 2016: 88 · 2015: 75 · 2014: 120 · 2013: 69 · 2012: 71
FWCI
40.08
Type
journal article
Language
en
Open access
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Georgia Cancer Coalition
  • National Institutes of Health (DP5OD012198)
  • National Institute of General Medical Sciences (T32GM008169)
  • National Institute of Allergy and Infectious Diseases (R01AI030363, R01AI20211, R01AI020211, R56AI030363, R21AI030363, AI30363)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords
caspase-8, necroptosis, embryonic lethality, death receptor signaling, FADD, Fas, RIPK1, apoptosis, lymphoid development, innate immunity, programmed cell death
MeSH terms
Animals, Cell Line, Embryo, Mammalian, Female, Immunocompetence, Lymphatic Diseases, Male, Mice, Inbred C57BL, Necrosis, Apoptosis, Gene Deletion, Mice, Knockout, GTPase-Activating Proteins, Embryo Loss, Mice, Caspase 8, Receptor-Interacting Protein Serine-Threonine Kinases, Caspase Inhibitors

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review