Cargando…
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...
Autores principales: | , , , , , , , , |
---|---|
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 |
_version_ | 1783527750288539648 |
---|---|
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. |
format | Online Article Text |
id | pubmed-7190755 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT shiyuheng upstreamorfspreventmavsspontaneousaggregationandregulateinnateimmunehomeostasis AT wujing upstreamorfspreventmavsspontaneousaggregationandregulateinnateimmunehomeostasis AT zhongtiansheng upstreamorfspreventmavsspontaneousaggregationandregulateinnateimmunehomeostasis AT zhuwenting upstreamorfspreventmavsspontaneousaggregationandregulateinnateimmunehomeostasis AT sheguolan upstreamorfspreventmavsspontaneousaggregationandregulateinnateimmunehomeostasis AT tanghao upstreamorfspreventmavsspontaneousaggregationandregulateinnateimmunehomeostasis AT duwei upstreamorfspreventmavsspontaneousaggregationandregulateinnateimmunehomeostasis AT yebangce upstreamorfspreventmavsspontaneousaggregationandregulateinnateimmunehomeostasis AT qinan upstreamorfspreventmavsspontaneousaggregationandregulateinnateimmunehomeostasis |