title: Deficiency of the adaptor protein SLy1 results in a natural killer cell ribosomopathy affecting tumor clearance.
abstract: Individuals with robust natural killer (NK) cell function incur lower rates of malignancies. To expand our understanding of genetic factors contributing to this phenomenon, we analyzed NK cells from cancer resistant and susceptible strains of mice. We identified a correlation between NK levels of the X-chromosome-located adaptor protein SLy1 and immunologic susceptibility to cancer. Unlike the case for T or B lymphocytes, where SLy1 shuttles between the cytoplasm and nucleus to facilitate signal transduction, in NK cells SLy1 functions as a ribosomal protein and is located solely in the cytoplasm. In its absence, ribosomal instability results in p53-mediated NK cell senescence and decreased clearance of malignancies. NK defects are reversible under inflammatory conditions and viral clearance is not impacted by SLy1 deficiency. Our work defines a previously unappreciated X-linked ribosomopathy that results in a specific and subtle NK cell dysfunction leading to immunologic susceptibility to cancer.
authors.affiliation: Department of Surgery, Washington University School of Medicine , St. Louis, MO, USA.
authors.forename: Saeed
authors.initials: S
authors.lastname: Arefanian
authors.affiliation: Department of Pharmacology and Experimental Therapy, Institute for Pharmacology and Toxicology, University of Tübingen , Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Schäll
authors.affiliation: Department of Surgery, Washington University School of Medicine , St. Louis, MO, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Chang
authors.affiliation: Department of Surgery, Washington University School of Medicine , St. Louis, MO, USA.
authors.forename: Reza
authors.initials: R
authors.lastname: Ghasemi
authors.affiliation: Department of Surgery, Washington University School of Medicine , St. Louis, MO, USA.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Higashikubo
authors.affiliation: Department of Surgery, Washington University School of Medicine , St. Louis, MO, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Zheleznyak
authors.affiliation: Department of Surgery, Washington University School of Medicine , St. Louis, MO, USA.
authors.forename: Yizhan
authors.identifier: 0000-0001-7627-6423
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Genome Technology Access Center at Department of Genetics, Washington University School of Medicine , St. Louis, MO, USA.
authors.forename: Jinsheng
authors.identifier: 0000-0003-3377-4304
authors.initials: J
authors.lastname: Yu
authors.affiliation: Program in Molecular and Computational Biology, University of Southern California , Los Angeles, CA, USA.
authors.forename: Hosseinali
authors.initials: H
authors.lastname: Asgharian
authors.affiliation: Department of Surgery, Washington University School of Medicine , St. Louis, MO, USA.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Gelman
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kreisel
authors.affiliation: Department of Pediatrics, Washington University in St. Louis , St. Louis, MO, USA.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: French
authors.affiliation: Department of Biology, Washington University in St. Louis , St. Louis, MO, USA.
authors.forename: Hani
authors.initials: H
authors.lastname: Zaher
authors.affiliation: Department of Internal Medicine , St. Louis, MO, USA.
authors.forename: Beatrice
authors.identifier: 0000-0002-6389-561X
authors.initials: B
authors.lastname: Plougastel-Douglas
authors.affiliation: Department of Internal Medicine , St. Louis, MO, USA.
authors.forename: Leonard
authors.identifier: 0000-0003-0138-0984
authors.initials: L
authors.lastname: Maggi
authors.affiliation: Department of Internal Medicine, St. Louis, MO, USA; The Howard Hughes Institute of Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Wayne
authors.initials: W
authors.lastname: Yokoyama
authors.affiliation: Department of Pharmacology and Experimental Therapy, Institute for Pharmacology and Toxicology, University of Tübingen , Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Beer-Hammer
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA; The Alvin Siteman Cancer Center of Washington University School of Medicine, St. Louis, MO, USA; The John Cochran VA Medical Center, St. Louis, MO, USA.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Krupnick
keywords: Immunosurveillance; lung cancer; natural killer cells; ribosomopathy