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Blood, 5 November 2009, Vol. 114, No. 19, pp. 4117-4127. Prepublished online as a Blood First Edition Paper on August 24, 2009; DOI 10.1182/blood-2009-06-225359. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2009-06-225359v1 114/19/4117    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Wood, S. M. Articles by Bryceson, Y. T. PubMed PubMed Citation Articles by Wood, S. M. Articles by Bryceson, Y. T. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Different NK cell–activating receptors preferentially recruit Rab27a or Munc13-4 to perforin-containing granules for cytotoxicity Stephanie M. Wood1,2, Marie Meeths3,4, Samuel C. C. Chiang1, Anne Grete Bechensteen5, Jaap J. Boelens6, Carsten Heilmann7, Hisanori Horiuchi8, Steen Rosthøj9, Olga Rutynowska10, Jacek Winiarski11, Jennifer L. Stow2, Magnus Nordenskjöld4, Jan-Inge Henter3, Hans-Gustaf Ljunggren1, and Yenan T. Bryceson1 1 Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; 2 Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia; 3 Childhood Cancer Research Unit, Department of Woman and Child Health and 4 Clinical Genetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden; 5 Department of Pediatrics, Ullevål University Hospital, Oslo, Norway; 6 Department of Immunology/Hematology and Bone Marrow Transplantation, University Medical Center Utrecht/Wilhelmina Children's Hospital, Department of Pediatrics/Stem Cell Transplantation Unit, Utrecht, The Netherlands; 7 Pediatric Clinic, Copenhagen University Hospital, Copenhagen, Denmark; 8 Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan; 9 Pediatric Department, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark; 10 Department of Oncology, Children's Memorial Health Institute, Warsaw, Poland; and 11 Department of Pediatrics, Clintec, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden The autosomal recessive immunodeficiencies Griscelli syndrome type 2 (GS2) and familial hemophagocytic lymphohistiocytosis type 3 (FHL3) are associated with loss-of-function mutations in RAB27A (encoding Rab27a) and UNC13D (encoding Munc13-4). Munc13-4 deficiency abrogates NK-cell release of perforin-containing lytic granules induced by signals for natural and antibody-dependent cellular cytotoxicity. We demonstrate here that these signals fail to induce degranulation in resting NK cells from Rab27a-deficient patients. In resting NK cells from healthy subjects, endogenous Rab27a and Munc13-4 do not colocalize extensively with perforin. However, phorbol 12-myristate 13-acetate and ionomycin stimulation or conjugation to susceptible target cells induced myosin-dependent colocalization of Rab27a and Munc13-4 with perforin. Unexpectedly, individual engagement of receptors leukocyte functional antigen-1, NKG2D, or 2B4 induced colocalization of Rab27a, but not Munc13-4, with perforin. Conversely, engagement of antibody-dependent cellular cytotoxicity receptor CD16 induced colocalization of Munc13-4, but not Rab27a, with perforin. Furthermore, colocalization of Munc13-4 with perforin was Rab27a-dependent. In conclusion, Rab27a or Munc13-4 recruitment to lytic granules is preferentially regulated by different receptor signals, demonstrating that individual target cell ligands regulate discrete molecular events for lytic granule maturation. The data suggest Rab27a facilitates degranulation at an early step yet highlight a reciprocal relationship between Munc13-4 and Rab27a for degranulation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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