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Modulation of Extracellular ISG15 Signaling by Pathogens and Viral Effector Proteins

ISG15 is a ubiquitin-like modifier that also functions extracellularly, signaling through the LFA-1 integrin to promote interferon (IFN)-γ release from natural killer (NK) and T cells. The signals that lead to the production of extracellular ISG15 and the relationship between its two core functions...

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Autores principales: Swaim, Caleb D., Canadeo, Larissa A., Monte, Kristen J., Khanna, Swati, Lenschow, Deborah J., Huibregtse, Jon M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Author(s). 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297157/
https://www.ncbi.nlm.nih.gov/pubmed/32553163
http://dx.doi.org/10.1016/j.celrep.2020.107772
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author Swaim, Caleb D.
Canadeo, Larissa A.
Monte, Kristen J.
Khanna, Swati
Lenschow, Deborah J.
Huibregtse, Jon M.
author_facet Swaim, Caleb D.
Canadeo, Larissa A.
Monte, Kristen J.
Khanna, Swati
Lenschow, Deborah J.
Huibregtse, Jon M.
author_sort Swaim, Caleb D.
collection PubMed
description ISG15 is a ubiquitin-like modifier that also functions extracellularly, signaling through the LFA-1 integrin to promote interferon (IFN)-γ release from natural killer (NK) and T cells. The signals that lead to the production of extracellular ISG15 and the relationship between its two core functions remain unclear. We show that both epithelial cells and lymphocytes can secrete ISG15, which then signals in either an autocrine or paracrine manner to LFA-1-expressing cells. Microbial pathogens and Toll-like receptor (TLR) agonists result in both IFN-β-dependent and -independent secretion of ISG15, and residues required for ISG15 secretion are mapped. Intracellular ISGylation inhibits secretion, and viral effector proteins, influenza B NS1, and viral de-ISGylases, including SARS-CoV-2 PL(pro), have opposing effects on secretion of ISG15. These results establish extracellular ISG15 as a cytokine-like protein that bridges early innate and IFN-γ-dependent immune responses, and indicate that pathogens have evolved to differentially inhibit the intracellular and extracellular functions of ISG15.
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spelling pubmed-72971572020-06-17 Modulation of Extracellular ISG15 Signaling by Pathogens and Viral Effector Proteins Swaim, Caleb D. Canadeo, Larissa A. Monte, Kristen J. Khanna, Swati Lenschow, Deborah J. Huibregtse, Jon M. Cell Rep Article ISG15 is a ubiquitin-like modifier that also functions extracellularly, signaling through the LFA-1 integrin to promote interferon (IFN)-γ release from natural killer (NK) and T cells. The signals that lead to the production of extracellular ISG15 and the relationship between its two core functions remain unclear. We show that both epithelial cells and lymphocytes can secrete ISG15, which then signals in either an autocrine or paracrine manner to LFA-1-expressing cells. Microbial pathogens and Toll-like receptor (TLR) agonists result in both IFN-β-dependent and -independent secretion of ISG15, and residues required for ISG15 secretion are mapped. Intracellular ISGylation inhibits secretion, and viral effector proteins, influenza B NS1, and viral de-ISGylases, including SARS-CoV-2 PL(pro), have opposing effects on secretion of ISG15. These results establish extracellular ISG15 as a cytokine-like protein that bridges early innate and IFN-γ-dependent immune responses, and indicate that pathogens have evolved to differentially inhibit the intracellular and extracellular functions of ISG15. The Author(s). 2020-06-16 2020-06-16 /pmc/articles/PMC7297157/ /pubmed/32553163 http://dx.doi.org/10.1016/j.celrep.2020.107772 Text en © 2020 The Author(s) Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
spellingShingle Article
Swaim, Caleb D.
Canadeo, Larissa A.
Monte, Kristen J.
Khanna, Swati
Lenschow, Deborah J.
Huibregtse, Jon M.
Modulation of Extracellular ISG15 Signaling by Pathogens and Viral Effector Proteins
title Modulation of Extracellular ISG15 Signaling by Pathogens and Viral Effector Proteins
title_full Modulation of Extracellular ISG15 Signaling by Pathogens and Viral Effector Proteins
title_fullStr Modulation of Extracellular ISG15 Signaling by Pathogens and Viral Effector Proteins
title_full_unstemmed Modulation of Extracellular ISG15 Signaling by Pathogens and Viral Effector Proteins
title_short Modulation of Extracellular ISG15 Signaling by Pathogens and Viral Effector Proteins
title_sort modulation of extracellular isg15 signaling by pathogens and viral effector proteins
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297157/
https://www.ncbi.nlm.nih.gov/pubmed/32553163
http://dx.doi.org/10.1016/j.celrep.2020.107772
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