Deficiency of the adaptor protein SLy1 results in a natural killer cell ribosomopathy affecting tumor clearance

Saeed Arefanian, Daniel Schäll, Stephanie Chang, Reza Ghasemi, Ryuji Higashikubo, Alex Zheleznyak, Yizhan Guo, Jinsheng Yu, Hosseinali Asgharian, Wenjun Li, Andrew E. Gelman, Daniel Kreisel, Anthony R. French, Hani Zaher, Beatrice Plougastel-Douglas, Leonard Maggi, Wayne Yokoyama, Sandra Beer-Hammer, Alexander S. Krupnick

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish
Article numbere1238543
JournalOncoImmunology
Volume5
Issue number12
DOIs
StatePublished - Dec 1 2016

Keywords

  • Immunosurveillance
  • lung cancer
  • natural killer cells
  • ribosomopathy

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