Modulation of Extracellular ISG15 Signaling by Pathogens and Viral Effector Proteins
| Autor: | Caleb D. Swaim, Jon M. Huibregtse, Swati Khanna, Deborah J. Lenschow, Kristen Monte, Larissa A. Canadeo |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
ISG15 ERVE Nairovirus vOTU SARS-CoV-2/COVID-19 PLpro Viral Nonstructural Proteins Article General Biochemistry Genetics and Molecular Biology foot and mouth disease virus Lbpro Interferon-gamma Jurkat Cells Mice 03 medical and health sciences Paracrine signalling 0302 clinical medicine Interferon interferon-γ Influenza Human Extracellular medicine Animals Humans Secretion TLRs Typhoid Fever Autocrine signalling lcsh:QH301-705.5 Ubiquitins Mycobacterium Infections Effector Chemistry interferon-α/β Pathogen-Associated Molecular Pattern Molecules Cell biology Mice Inbred C57BL HEK293 Cells 030104 developmental biology lcsh:Biology (General) Cytokines Signal transduction influenza B NS1 030217 neurology & neurosurgery LFA-1 Signal Transduction medicine.drug |
| Zdroj: | Cell Reports Cell Reports, Vol 31, Iss 11, Pp 107772-(2020) |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2020.107772 |
| Popis: | Summary 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 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. Graphical Abstract Highlights • ISG15 is released from multiple cell types to signal to LFA-1-expressing lymphocytes • Mutational analysis separates ISG15 secretion from LFA-1 binding and ISGylation • Intracellular conjugation of ISG15 negatively modulates its secretion • Viral de-ISGylases, including SARS-CoV-2 PLpro, positively modulate ISG15 secretion Swaim et al. characterize cell types and immune agonists that stimulate ISG15 secretion and signaling to lymphocytes. Intracellular conjugation of ISG15 is shown to inhibit secretion, whereas viral de-ISGylating enzymes, including SARS-CoV-2 PLpro, enhance ISG15 secretion, suggesting a potential role for ISG15 in pro-inflammatory responses associated with viral infections. |
| Databáze: | OpenAIRE |
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