期刊
NUCLEIC ACIDS RESEARCH
卷 47, 期 16, 页码 8838-8859出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkz628
关键词
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资金
- Japan Society for the Promotion of Science (JSPS) KAKENHI [18H05278]
- AMED-CREST from Japan Agency for Medical Research and Development
- AMED-FORCE from Japan Agency for Medical Research and Development
- JSPS throughCore-to-Core Program
- JSPS KAKENHI [16K08832, 19H03488, 15KT0084]
- Takeda Science Foundation
- Uehara Memorial Foundation
- Shimizu Foundation for Immunology and Neuroscience
- Naito Foundation
- Senri Life Science Foundation
- Nakajima Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Project for Cancer Research and Therapeutic Evolution (P-CREATE), AMED
- Cooperative Research Program of Institute for Protein Research, Osaka University [CR-17-01]
- RIKEN Epigenome and Single Cell Project Grants
- Nagase Science Technology Foundation
- Astellas Foundation for Research on Metabolic Disorders
- Daiichi Sankyo Foundation of Life Science
- JSPS [18H05278]
- [221S0002]
- [16H06279]
- Grants-in-Aid for Scientific Research [15KT0084, 18H05278, 16K08832, 19H03488] Funding Source: KAKEN
Regnase-1-mediated mRNA decay (RMD), in which inflammatory mRNAs harboring specific stem-loop structures are degraded, is a critical part of proper immune homeostasis. Prior to initial translation, Regnase-1 associates with target stem-loops but does not carry out endoribonucleolytic cleavage. Single molecule imaging revealed that UPF1 is required to first unwind the stem-loops, thus licensing Regnase-1 to proceed with RNA degradation. Following translation, Regnase-1 physically associates with UPF1 using two distinct points of interaction: The Regnase-1 RNase domain binds to SMG1-phosphorylated residue T28 in UPF1; in addition, an intrinsically disordered segment in Regnase-1 binds to the UPF1 RecA domain, enhancing the helicase activity of UPF1. The SMG1-UPF1-Regnase-1 axis targets pioneer rounds of translation and is critical for rapid resolution of inflammation through restriction of the number of proteins translated by a given mRNA. Furthermore, small-molecule inhibition of SMG1 prevents RNA unwinding in dendritic cells, allowing post-transcriptional control of innate immune responses.
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