RIP3-mediated necroptosis is regulated by inter-filament assembly of RIP homotypic interaction motif
2021-01
Source PublicationCELL DEATH AND DIFFERENTIATION
ISSN1350-9047
EISSN1476-5403
Status已发表
DOI10.1038/s41418-020-0598-9
Abstract

 Necroptosis is mediated by signaling complexes called necrosomes, which contain receptor-interacting protein 3 (RIP3) and upstream effectors, such as RIP1. In necrosomes, the RIP homotypic interaction motif (RHIM) of RIP3 and RIP1 forms amyloidal complex. But how the amyloidal necrosomes control RIP3 activation and cell necroptosis has not been determined. Here, we showed that RIP3 amyloid fibrils could further assemble into large fibrillar networks which presents as cellular puncta during necroptosis. A viral RHIM-containing necroptosis inhibitor M45 could form heteroamyloid with RIP3 in cells and prevent RIP3 puncta formation and cell necroptosis. We characterized mutual antagonism between RIP3–RHIM and M45–RHIM in necroptosis regulation, which was caused by distinct inter-filament interactions in RIP3, M45 amyloids revealed with atomic force microscopy. Moreover, double mutations Asn464 and Met468 in RIP3–RHIM to Asp disrupted RIP3 kinase-dependent necroptosis. While the mutant RIP3(N464D/M468D) could form amyloid as wild type upon necroptosis induction. Based on these results, we propose that RIP3 amyloid formation is required but not sufficient in necroptosis signaling, the ordered inter-filament assembly of RIP3 is critical in RIP3 amyloid mediated kinase activation and cell necroptosis.

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Indexed BySCI ; SCIE
Funding ProjectAnalytical Instrumentation Center, SPST, ShanghaiTech University[SPST-AIC10112914] ; National Natural Science Foundation of China[31770790][31571427]
WOS Research AreaBiochemistry & Molecular Biology ; Cell Biology
WOS SubjectBiochemistry & Molecular Biology ; Cell Biology
WOS IDWOS:000554349600003
PublisherNATURE PUBLISHING GROUP
WOS KeywordPROGRAMMED NECROSIS ; CELL-DEATH ; VIRUS ; CYTOMEGALOVIRUS ; INFLAMMATION
Original Document TypeArticle
Citation statistics
Document Type期刊论文
Identifierhttps://kms.shanghaitech.edu.cn/handle/2MSLDSTB/122495
Collection生命科学与技术学院
生命科学与技术学院_PI研究组_王华翌组
生命科学与技术学院_PI研究组_陆珺霞组
生命科学与技术学院_公共科研平台_分子细胞学平台
生命科学与技术学院_硕士生
生命科学与技术学院_博士生
Co-First AuthorWu, Xialian
Corresponding AuthorLu, Junxia; Wang, Huayi
Affiliation
1.ShanghaiTech Univ, Sch Life Sci & Technol, 393 Middle Huaxia Rd, Shanghai 201210, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, Ctr Excellence Mol Cell Sci, 320 Yueyang Rd, Shanghai 200031, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100864, Peoples R China
First Author AffilicationSchool of Life Science and Technology
Corresponding Author AffilicationSchool of Life Science and Technology
First Signature AffilicationSchool of Life Science and Technology
Recommended Citation
GB/T 7714
Hu, Hong,Wu, Xialian,Wu, Guoxiang,et al. RIP3-mediated necroptosis is regulated by inter-filament assembly of RIP homotypic interaction motif[J]. CELL DEATH AND DIFFERENTIATION,2021.
APA Hu, Hong.,Wu, Xialian.,Wu, Guoxiang.,Nan, Ning.,Zhang, Jing.,...&Wang, Huayi.(2021).RIP3-mediated necroptosis is regulated by inter-filament assembly of RIP homotypic interaction motif.CELL DEATH AND DIFFERENTIATION.
MLA Hu, Hong,et al."RIP3-mediated necroptosis is regulated by inter-filament assembly of RIP homotypic interaction motif".CELL DEATH AND DIFFERENTIATION (2021).
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