title: ISG15 deficiency and increased viral resistance in humans but not mice.
abstract: ISG15 is an interferon (IFN)-α/β-induced ubiquitin-like protein. It exists as a free molecule, intracellularly and extracellularly, and conjugated to target proteins. Studies in mice have demonstrated a role for Isg15 in antiviral immunity. By contrast, human ISG15 was shown to have critical immune functions, but not in antiviral immunity. Namely, free extracellular ISG15 is crucial in IFN-γ-dependent antimycobacterial immunity, while free intracellular ISG15 is crucial for USP18-mediated downregulation of IFN-α/β signalling. Here we describe ISG15-deficient patients who display no enhanced susceptibility to viruses in vivo, in stark contrast to Isg15-deficient mice. Furthermore, fibroblasts derived from ISG15-deficient patients display enhanced antiviral protection, and expression of ISG15 attenuates viral resistance to WT control levels. The species-specific gain-of-function in antiviral immunity observed in ISG15 deficiency is explained by the requirement of ISG15 to sustain USP18 levels in humans, a mechanism not operating in mice.
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Speer
authors.affiliation: Institut Pasteur, Cytokine Signalling Unit, CNRS URA 1961, 75724 Paris, France.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
authors.forename: Sofija
authors.initials: S
authors.lastname: Buta
authors.affiliation: Institut Pasteur, Cytokine Signalling Unit, CNRS URA 1961, 75724 Paris, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Payelle-Brogard
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Qian
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
authors.forename: Frederic
authors.initials: F
authors.lastname: Vigant
authors.affiliation: Institut Pasteur, Cytokine Signalling Unit, CNRS URA 1961, 75724 Paris, France.
authors.forename: Erminia
authors.initials: E
authors.lastname: Rubino
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Gardner
authors.affiliation: Department of Biology, University of Osnabrück, 49076 Osnabrück, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Wedeking
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Hermann
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
authors.forename: James
authors.identifier: 0000-0003-2077-6685
authors.initials: J
authors.lastname: Duehr
authors.affiliation: Immunology Division, Hacettepe University, Ihsan Dogramaci Children's Hospital, 06100 Ankara, Turkey.
authors.forename: Ozden
authors.initials: O
authors.lastname: Sanal
authors.affiliation: Immunology Division, Hacettepe University, Ihsan Dogramaci Children's Hospital, 06100 Ankara, Turkey.
authors.forename: Ilhan
authors.initials: I
authors.lastname: Tezcan
authors.affiliation: Division of Infectious Diseases and Clinical Immunology, Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, 4739 Teheran, Iran.
authors.forename: Nahal
authors.initials: N
authors.lastname: Mansouri
authors.affiliation: Division of Infectious Diseases and Clinical Immunology, Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, 4739 Teheran, Iran.
authors.forename: Payam
authors.initials: P
authors.lastname: Tabarsi
authors.affiliation: Division of Infectious Diseases and Clinical Immunology, Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, 4739 Teheran, Iran.
authors.forename: Davood
authors.initials: D
authors.lastname: Mansouri
authors.affiliation: Institut Pasteur, Cytokine Signalling Unit, CNRS URA 1961, 75724 Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Francois-Newton
authors.affiliation: Institut Pasteur, Cytokine Signalling Unit, CNRS URA 1961, 75724 Paris, France.
authors.forename: Coralie F
authors.identifier: 0000-0003-3677-1280
authors.initials: CF
authors.lastname: Daussy
authors.affiliation: Department of Medicine and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Marisela R
authors.initials: MR
authors.lastname: Rodriguez
authors.affiliation: Department of Medicine and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Lenschow
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Freiberg
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
authors.forename: Domenico
authors.initials: D
authors.lastname: Tortorella
authors.affiliation: Department of Biology, University of Osnabrück, 49076 Osnabrück, Germany.
authors.forename: Jacob
authors.initials: J
authors.lastname: Piehler
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
authors.forename: Benhur
authors.initials: B
authors.lastname: Lee
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.affiliation: Institut Pasteur, Cytokine Signalling Unit, CNRS URA 1961, 75724 Paris, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pellegrini
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
authors.forename: Dusan
authors.initials: D
authors.lastname: Bogunovic
mesh_terms: D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007372:Interferons / Q000378:metabolism; D051379:Mice; D061251:Primary Cell Culture; D043222:Ubiquitin Thiolesterase / Q000378:metabolism; D014452:Ubiquitins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014777:Virus Diseases / Q000276:immunology*
chemical_list: D016207:Cytokines; C489550:G1p2 protein, mouse; D014452:Ubiquitins; C074034:ISG15 protein, human; D007372:Interferons; C118306:Usp18 protein, mouse; D043222:Ubiquitin Thiolesterase