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Lyn kinase regulates egress of flaviviruses in autophagosome-derived organelles

Among the various host cellular processes that are hijacked by flaviviruses, few mechanisms have been described with regard to viral egress. Here we investigate how flaviviruses exploit Src family kinases (SFKs) for exit from infected cells. We identify Lyn as a critical component for secretion of D...

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Autores principales: Li, Ming Yuan, Naik, Trupti Shivaprasad, Siu, Lewis Yu Lam, Acuto, Oreste, Spooner, Eric, Wang, Peigang, Yang, Xiaohan, Lin, Yongping, Bruzzone, Roberto, Ashour, Joseph, Evans, Matthew J, Sanyal, Sumana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564011/
https://www.ncbi.nlm.nih.gov/pubmed/33060596
http://dx.doi.org/10.1038/s41467-020-19028-w
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author Li, Ming Yuan
Naik, Trupti Shivaprasad
Siu, Lewis Yu Lam
Acuto, Oreste
Spooner, Eric
Wang, Peigang
Yang, Xiaohan
Lin, Yongping
Bruzzone, Roberto
Ashour, Joseph
Evans, Matthew J
Sanyal, Sumana
author_facet Li, Ming Yuan
Naik, Trupti Shivaprasad
Siu, Lewis Yu Lam
Acuto, Oreste
Spooner, Eric
Wang, Peigang
Yang, Xiaohan
Lin, Yongping
Bruzzone, Roberto
Ashour, Joseph
Evans, Matthew J
Sanyal, Sumana
author_sort Li, Ming Yuan
collection PubMed
description Among the various host cellular processes that are hijacked by flaviviruses, few mechanisms have been described with regard to viral egress. Here we investigate how flaviviruses exploit Src family kinases (SFKs) for exit from infected cells. We identify Lyn as a critical component for secretion of Dengue and Zika infectious particles and their corresponding virus like particles (VLPs). Pharmacological inhibition or genetic depletion of the SFKs, Lyn in particular, block virus secretion. Lyn(−/−) cells are impaired in virus release and are rescued when reconstituted with wild-type Lyn, but not a kinase- or palmitoylation-deficient Lyn mutant. We establish that virus particles are secreted in two distinct populations – one as free virions and the other enclosed within membranes. Lyn is critical for the latter, which consists of proteolytically processed, infectious virus progenies within autophagosome-derived vesicles. This process depends on Ulk1, Rab GTPases and SNARE complexes implicated in secretory but not degradative autophagy and occur with significantly faster kinetics than the conventional secretory pathway. Our study reveals a previously undiscovered Lyn-dependent exit route of flaviviruses in LC3+ secretory organelles that enables them to evade circulating antibodies and might affect tissue tropism.
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spelling pubmed-75640112020-10-19 Lyn kinase regulates egress of flaviviruses in autophagosome-derived organelles Li, Ming Yuan Naik, Trupti Shivaprasad Siu, Lewis Yu Lam Acuto, Oreste Spooner, Eric Wang, Peigang Yang, Xiaohan Lin, Yongping Bruzzone, Roberto Ashour, Joseph Evans, Matthew J Sanyal, Sumana Nat Commun Article Among the various host cellular processes that are hijacked by flaviviruses, few mechanisms have been described with regard to viral egress. Here we investigate how flaviviruses exploit Src family kinases (SFKs) for exit from infected cells. We identify Lyn as a critical component for secretion of Dengue and Zika infectious particles and their corresponding virus like particles (VLPs). Pharmacological inhibition or genetic depletion of the SFKs, Lyn in particular, block virus secretion. Lyn(−/−) cells are impaired in virus release and are rescued when reconstituted with wild-type Lyn, but not a kinase- or palmitoylation-deficient Lyn mutant. We establish that virus particles are secreted in two distinct populations – one as free virions and the other enclosed within membranes. Lyn is critical for the latter, which consists of proteolytically processed, infectious virus progenies within autophagosome-derived vesicles. This process depends on Ulk1, Rab GTPases and SNARE complexes implicated in secretory but not degradative autophagy and occur with significantly faster kinetics than the conventional secretory pathway. Our study reveals a previously undiscovered Lyn-dependent exit route of flaviviruses in LC3+ secretory organelles that enables them to evade circulating antibodies and might affect tissue tropism. Nature Publishing Group UK 2020-10-15 /pmc/articles/PMC7564011/ /pubmed/33060596 http://dx.doi.org/10.1038/s41467-020-19028-w Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Li, Ming Yuan
Naik, Trupti Shivaprasad
Siu, Lewis Yu Lam
Acuto, Oreste
Spooner, Eric
Wang, Peigang
Yang, Xiaohan
Lin, Yongping
Bruzzone, Roberto
Ashour, Joseph
Evans, Matthew J
Sanyal, Sumana
Lyn kinase regulates egress of flaviviruses in autophagosome-derived organelles
title Lyn kinase regulates egress of flaviviruses in autophagosome-derived organelles
title_full Lyn kinase regulates egress of flaviviruses in autophagosome-derived organelles
title_fullStr Lyn kinase regulates egress of flaviviruses in autophagosome-derived organelles
title_full_unstemmed Lyn kinase regulates egress of flaviviruses in autophagosome-derived organelles
title_short Lyn kinase regulates egress of flaviviruses in autophagosome-derived organelles
title_sort lyn kinase regulates egress of flaviviruses in autophagosome-derived organelles
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564011/
https://www.ncbi.nlm.nih.gov/pubmed/33060596
http://dx.doi.org/10.1038/s41467-020-19028-w
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