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Upstream ORFs Prevent MAVS Spontaneous Aggregation and Regulate Innate Immune Homeostasis

The monomer-to-filament transition of MAVS is essential for the RIG-I/MDA5-mediated antiviral signaling. In quiescent cells, monomeric MAVS is under strict regulation for preventing its spontaneous aggregation, which would result in dysregulated interferon (IFN-α/β) production and autoimmune disease...

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Autores principales: Shi, Yuheng, Wu, Jing, Zhong, Tiansheng, Zhu, Wenting, She, Guolan, Tang, Hao, Du, Wei, Ye, Bang-Ce, Qi, Nan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190755/
https://www.ncbi.nlm.nih.gov/pubmed/32339989
http://dx.doi.org/10.1016/j.isci.2020.101059
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author Shi, Yuheng
Wu, Jing
Zhong, Tiansheng
Zhu, Wenting
She, Guolan
Tang, Hao
Du, Wei
Ye, Bang-Ce
Qi, Nan
author_facet Shi, Yuheng
Wu, Jing
Zhong, Tiansheng
Zhu, Wenting
She, Guolan
Tang, Hao
Du, Wei
Ye, Bang-Ce
Qi, Nan
author_sort Shi, Yuheng
collection PubMed
description The monomer-to-filament transition of MAVS is essential for the RIG-I/MDA5-mediated antiviral signaling. In quiescent cells, monomeric MAVS is under strict regulation for preventing its spontaneous aggregation, which would result in dysregulated interferon (IFN-α/β) production and autoimmune diseases like systemic lupus erythematosus. However, the detailed mechanism by which MAVS is kept from spontaneous aggregation remains largely unclear. Here, we show that upstream open reading frames (uORFs) within the MAVS transcripts exert a post-transcriptional regulation for preventing MAVS spontaneous aggregation and auto-activation. Mechanistically, we demonstrate that uORFs are cis-acting elements initiating leaky ribosome scanning of the downstream ORF codons, thereby repressing the full-length MAVS translation. We further uncover that endogenous MAVS generated from the uORF-deprived transcript spontaneously aggregates, triggering the Nix-mediated mitophagic clearance of damaged mitochondria and aggregated MAVS. Our findings reveal the uORF-mediated quantity and quality control of MAVS, which prevents aberrant protein aggregation and maintains innate immune homeostasis.
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spelling pubmed-71907552020-05-04 Upstream ORFs Prevent MAVS Spontaneous Aggregation and Regulate Innate Immune Homeostasis Shi, Yuheng Wu, Jing Zhong, Tiansheng Zhu, Wenting She, Guolan Tang, Hao Du, Wei Ye, Bang-Ce Qi, Nan iScience Article The monomer-to-filament transition of MAVS is essential for the RIG-I/MDA5-mediated antiviral signaling. In quiescent cells, monomeric MAVS is under strict regulation for preventing its spontaneous aggregation, which would result in dysregulated interferon (IFN-α/β) production and autoimmune diseases like systemic lupus erythematosus. However, the detailed mechanism by which MAVS is kept from spontaneous aggregation remains largely unclear. Here, we show that upstream open reading frames (uORFs) within the MAVS transcripts exert a post-transcriptional regulation for preventing MAVS spontaneous aggregation and auto-activation. Mechanistically, we demonstrate that uORFs are cis-acting elements initiating leaky ribosome scanning of the downstream ORF codons, thereby repressing the full-length MAVS translation. We further uncover that endogenous MAVS generated from the uORF-deprived transcript spontaneously aggregates, triggering the Nix-mediated mitophagic clearance of damaged mitochondria and aggregated MAVS. Our findings reveal the uORF-mediated quantity and quality control of MAVS, which prevents aberrant protein aggregation and maintains innate immune homeostasis. Elsevier 2020-04-13 /pmc/articles/PMC7190755/ /pubmed/32339989 http://dx.doi.org/10.1016/j.isci.2020.101059 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Shi, Yuheng
Wu, Jing
Zhong, Tiansheng
Zhu, Wenting
She, Guolan
Tang, Hao
Du, Wei
Ye, Bang-Ce
Qi, Nan
Upstream ORFs Prevent MAVS Spontaneous Aggregation and Regulate Innate Immune Homeostasis
title Upstream ORFs Prevent MAVS Spontaneous Aggregation and Regulate Innate Immune Homeostasis
title_full Upstream ORFs Prevent MAVS Spontaneous Aggregation and Regulate Innate Immune Homeostasis
title_fullStr Upstream ORFs Prevent MAVS Spontaneous Aggregation and Regulate Innate Immune Homeostasis
title_full_unstemmed Upstream ORFs Prevent MAVS Spontaneous Aggregation and Regulate Innate Immune Homeostasis
title_short Upstream ORFs Prevent MAVS Spontaneous Aggregation and Regulate Innate Immune Homeostasis
title_sort upstream orfs prevent mavs spontaneous aggregation and regulate innate immune homeostasis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190755/
https://www.ncbi.nlm.nih.gov/pubmed/32339989
http://dx.doi.org/10.1016/j.isci.2020.101059
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