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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.
  • Swaim CD; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA.
  • Canadeo LA; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA.
  • Monte KJ; Departments of Internal Medicine and Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • Khanna S; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA.
  • Lenschow DJ; Departments of Internal Medicine and Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • Huibregtse JM; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA. Electronic address: huibregtse@austin.utexas.edu.
Cell Rep ; 31(11): 107772, 2020 06 16.
Article in English | MEDLINE | ID: covidwho-1385222
ABSTRACT
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-ß-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 PLpro, 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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Full text: Available Collection: International databases Database: MEDLINE Main subject: Ubiquitins / Signal Transduction / Cytokines Type of study: Experimental Studies Limits: Animals / Humans Language: English Journal: Cell Rep Year: 2020 Document Type: Article Affiliation country: J.CELREP.2020.107772

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Ubiquitins / Signal Transduction / Cytokines Type of study: Experimental Studies Limits: Animals / Humans Language: English Journal: Cell Rep Year: 2020 Document Type: Article Affiliation country: J.CELREP.2020.107772