Identification of MYC as an antinecroptotic protein that stifles RIPK1-RIPK3 complex formation

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Title
Identification of MYC as an antinecroptotic protein that stifles RIPK1-RIPK3 complex formation
Author(s)
D Seong; M Jeong; Jinho Seo; Ji-Yoon Lee; C H Hwang; Ho Chul Shin; J Y Shin; Y W Nam; J Y Jo; H Lee; H J Kim; H R Kim; J H Oh; S J Ha; Seung Jun Kim; J S Roe; W Kim; J W Cheong; Kwang-Hee BaeSang Chul Lee; A Oberst; P Vandenabeele; D H Shin; Eun-Woo Lee; J Song
Bibliographic Citation
Proceedings of National Academy of Sciences of United States of America, vol. 117, no. 33, pp. 19982-19993
Publication Year
2020
Abstract
The underlying mechanism of necroptosis in relation to cancer is still unclear. Here, MYC, a potent oncogene, is an antinecroptotic factor that directly suppresses the formation of the RIPK1-RIPK3 complex. Gene set enrichment analyses reveal that the MYC pathway is the most prominently down-regulated signaling pathway during necroptosis. Depletion or deletion of MYC promotes the RIPK1-RIPK3 interaction, thereby stabilizing the RIPK1 and RIPK3 proteins and facilitating necroptosis. Interestingly, MYC binds to RIPK3 in the cytoplasm and inhibits the interaction between RIPK1 and RIPK3 in vitro. Furthermore, MYC-nick, a truncated form that is mainly localized in the cytoplasm, prevented TNF-induced necroptosis. Finally, down-regulation of MYC enhances necroptosis in leukemia cells and suppresses tumor growth in a xenograft model upon treatment with birinapant and emricasan. MYC-mediated suppression of necroptosis is a mechanism of necroptosis resistance in cancer, and approaches targeting MYC to induce necroptosis represent an attractive therapeutic strategy for cancer.
Keyword
MYCRIPK3TNF-αnecroptosis
ISSN
0027-8424
Publisher
Natl Acad Sciences
DOI
http://dx.doi.org/10.1073/pnas.2000979117
Type
Article
Appears in Collections:
Aging Convergence Research Center > 1. Journal Articles
Critical Diseases Diagnostics Convergence Research Center > 1. Journal Articles
Division of Biomedical Research > Metabolic Regulation Research Center > 1. Journal Articles
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