Document Type

Article

Publication Date

2-11-2019

Comments

This article has been peer reviewed. It is the author’s final published version in Nature Communications, Volume 10, Issue 1, February 2019, Article number 705.

The published version is available at https://doi.org/10.1038/s41467-019-08584-5. Copyright © Dowling et al.

Publication made possible in part by support from the Thomas Jefferson University + Philadelphia University Open Access Fund

Abstract

TRADD is an adaptor for TNFR1-induced apoptosis and NFκB activation. However, TRADD-deficient mice undergo normal development and contain normal lymphoid populations, which contrasts with an embryonic defect in mice lacking FADD, the shared adaptor mediating apoptosis. Recent studies indicate FADD suppresses embryonic necroptosis mediated by RIPK1. TRADD was suggested to also mediate necroptosis. Here we report that targeting TRADD fails to rescue Fadd −/− embryos from necroptosis, and ablation of TRADD rescues Ripk1 −/− mice from perinatal lethality when RIPK3-mediated necroptosis is disabled. The resulting Ripk1 −/− Ripk3 −/− Tradd −/− mice survive until early adulthood, but die thereafter. A single allele of Tradd is optimal for survival of Ripk1 −/− Ripk3 −/− Tradd +/− mice. We show that TRADD plays a more dominating role in NFκB-signaling than RIPK1. While RIPK1 protects thymocytes from TNFα-induced apoptosis, TRADD promotes this process. The data demonstrate that TRADD is critical in perinatal and adult mice lacking RIPK1 and RIPK3, which has not been appreciated in prior studies.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

30741936

Language

English

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