title: NK Cell Maturation and Cytotoxicity Are Controlled by the Intramembrane Aspartyl Protease SPPL3.
abstract: NK cell maturation is critical for normal effector function and the innate immune response to tumors and pathogens. However, the molecular pathways that control NK cell maturation remain largely undefined. In this article, we investigate the role of SPPL3, an intramembrane aspartyl protease, in murine NK cell biology. We find that deletion of SPPL3 in the hematopoietic system reduces numbers of peripheral NK cells, clearance of MHC class I-deficient tumors in vivo, and cytotoxicity against tumor cells in vitro. This phenotype is concomitant with reduced numbers of CD27(+)CD11b(+) and CD27(-)CD11b(+) NK cells, indicating a requirement for SPPL3 in efficient NK cell maturation. NK cell-specific deletion of SPPL3 results in the same deficiencies, revealing a cell-autonomous role for SPPL3 in these processes. CRISPR/Cas9 genomic editing in murine zygotes was used to generate knockin mice with a catalytically compromised SPPL3 D271A allele. Mice engineered to express only SPPL3 D271A in NK cells phenocopy mice deleted for SPPL3, indicating a requirement for SPPL3 protease activity in NK cell biology. Our results identify SPPL3 as a cell-autonomous molecular determinant of NK cell maturation and expand the role of intramembrane aspartyl proteases in innate immunity.
authors: Department of Biological Chemistry, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors: Corinne E
authors: CE
authors: Hamblet
authors: Department of Biological Chemistry, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors: Stefanie L
authors: SL
authors: Makowski
authors: Department of Biological Chemistry, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors: Julia M
authors: JM
authors: Tritapoe
authors: Department of Biological Chemistry, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205 joel.pomerantz@jhmi.edu.
authors: Joel L
authors: http://orcid.org/0000-0002-5030-1018
authors: JL
authors: Pomerantz
mesh_terms: D000818:Animals; D057055:Aspartic Acid Proteases / Q000276:immunology*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000276:immunology*; D002462:Cell Membrane / Q000201:enzymology; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D055879:Gene Knock-In Techniques; D007113:Immunity, Innate / Q000276:immunology; D007694:Killer Cells, Natural / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction
chemical_list: D057055:Aspartic Acid Proteases