title: HkRP3 is a microtubule-binding protein regulating lytic granule clustering and NK cell killing.
abstract: NK cells provide host defense by killing viral-infected and cancerous cells through the secretion of preformed lytic granules. Polarization of the lytic granules toward the target cell is dependent on an intact microtubule (MT) network as well as MT motors. We have recently shown that DOCK8, a gene mutated in a primary immunodeficiency syndrome, is involved in NK cell killing in part through its effects on MT organizing center (MTOC) polarization. In this study, we identified Hook-related protein 3 (HkRP3) as a novel DOCK8- and MT-binding protein. We further show that HkRP3 is present in lytic granule fractions and interacts with the dynein motor complex and MTs. Significantly, depletion of HkPR3 impaired NK cell cytotoxicity, which could be attributed to a defect in not only MTOC polarity, but also impaired clustering of lytic granules around the MTOC. Our results demonstrate an important role for HkRP3 in regulating the clustering of lytic granules and MTOC repositioning during the development of NK cell-mediated killing.
authors.affiliation: Department of Immunology, Mayo Graduate School, College of Medicine, Mayo Clinic, Rochester, MN 55905;
authors.forename: Hyoungjun
authors.initials: H
authors.lastname: Ham
authors.affiliation: Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA 94158; and.
authors.forename: Walter
authors.initials: W
authors.lastname: Huynh
authors.affiliation: Department of Immunology, Mayo Graduate School, College of Medicine, Mayo Clinic, Rochester, MN 55905; Division of Oncology Research, Schulze Center for Novel Therapeutics, College of Medicine, Mayo Clinic, Rochester, MN 55905.
authors.forename: Renee A
authors.initials: RA
authors.lastname: Schoon
authors.affiliation: Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA 94158; and.
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Vale
authors.affiliation: Department of Immunology, Mayo Graduate School, College of Medicine, Mayo Clinic, Rochester, MN 55905; Division of Oncology Research, Schulze Center for Novel Therapeutics, College of Medicine, Mayo Clinic, Rochester, MN 55905 billadeau.daniel@mayo.edu.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Billadeau
mesh_terms: D002460:Cell Line; D004398:Dyneins / Q000276:immunology*; D020662:Guanine Nucleotide Exchange Factors / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008869:Microtubule-Associated Proteins / Q000276:immunology*; D022101:Microtubule-Organizing Center / Q000276:immunology*; D022142:Secretory Vesicles / Q000276:immunology*
chemical_list: C516591:DOCK8 protein, human; D020662:Guanine Nucleotide Exchange Factors; D008869:Microtubule-Associated Proteins; D004398:Dyneins