Ubiquitination of RIP1 Regulates an NF-κB-Independent Cell-Death Switch in TNF Signaling

O'Donnell, Marie Anne; Legarda-Addison, Diana; Skountzos, Penelopi; Yeh, Wen Chen; Ting, Adrian T.

doi:10.1016/j.cub.2007.01.027

Cited by 310NF-κB Signaling PathwaysCell death mechanisms and regulationImmune Response and Inflammation

Ubiquitination of RIP1 Regulates an NF-κB-Independent Cell-Death Switch in TNF Signaling

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O'Donnell, Marie Anne, Legarda-Addison, Diana, Skountzos, Penelopi, Yeh, Wen Chen, Ting, Adrian T.·2007·Current Biology

DOI 10.1016/j.cub.2007.01.027PMC PMC1868513

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Abstract

TNF receptor 1 (TNFR1) can trigger opposing responses within the same cell: a prosurvival response or a cell-death pathway [1, 2]. Cell survival requires NF-kappaB-mediated transcription of prosurvival genes [3-9]; apoptosis occurs if NF-kappaB signaling is blocked [5, 7-9]. Hence, activation of NF-kappaB acts as a cell-death switch during TNF signaling. This study demonstrates that the pathway includes another cell-death switch that is independent of NF-kappaB. We show that lysine 63-linked ubiquitination of RIP1 on lysine 377 inhibits TNF-induced apoptosis first through an NF-kappaB-independent mechanism and, subsequently, through an NF-kappaB-dependent mechanism. In contrast, in the absence of ubiquitination, RIP1 serves as a proapoptotic signaling molecule by engaging CASPASE-8. Therefore, RIP1 is a dual-function molecule that can be either prosurvival or prodeath depending on its ubiquitination state, and this serves as an NF-kappaB-independent cell-death switch early in TNF signaling. These results provide an explanation for the conflicting reports on the role of RIP1 in cell death; this role was previously suggested to be both prosurvival and prodeath [10-12]. Because TRAF2 is the E3 ligase for RIP1 [13], these observations provide an explanation for the NF-kappaB-independent antiapoptotic function previously described for TRAF2 [14-16].

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TNFR1 activation can have diverse outcomes depending on variables such as post-translational modification status of RIPK1, which impacts assembly of pro-survival vs pro-death signaling complexes.
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From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [323]

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Authors: O'Donnell, M. A., Legarda-Addison, D., Skountzos, P., Yeh, W. C., & Ting, A. T.
Affiliations: Icahn School of Medicine at Mount Sinai (US)
Amgen (United States) (US)
Corresponding author: Ting, Adrian T.
ORCID: Ting, Adrian T.
Venue: Current Biology
Publisher: Elsevier BV
Published: 2007-03
Volume: 17
Issue: 5
Pages: 418-424
ISSN: 0960-9822 (ISSN-L)
DOI: 10.1016/j.cub.2007.01.027
PMC: PMC1868513
OpenAlex: W2063211255
Cited by: 310
References: 32
Citations by year: 2026: 8 · 2025: 6 · 2024: 9 · 2023: 12 · 2022: 15 · 2021: 17 · 2020: 13 · 2019: 16 · 2018: 22 · 2017: 24 · 2016: 23 · 2015: 22 · 2014: 20 · 2013: 27 · 2012: 15
FWCI: 4.70
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 2330 d)
Locations: Current Biology (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health
U.S. Public Health Service (R21 57997)
National Institute of Allergy and Infectious Diseases (R21AI057997, R01 AI 52417, R01AI052417)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords: RIPK1, apoptosis, TRAF2, E3 ubiquitin ligase, caspase-8, survival signaling

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Ubiquitination of RIP1 Regulates an NF-κB-Independent Cell-Death Switch in TNF Signaling

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