Different NK cell-activating receptors preferentially recruit Rab27a or Munc13-4 to perforin-containing granules for cytotoxicity

Wood, S. M., Meeths, M, Chiang, S. C. C., Bechensteen, A. G., Boelens, J. J., Heilmann, C, Horiuchi, H, Rosthoj, S, Rutynowska, O, Winiarski, J, Stow, J. L., Nordenskjold, M, Henter, J. I., Ljunggren, H. G. and Bryceson, Y. T. (2009) Different NK cell-activating receptors preferentially recruit Rab27a or Munc13-4 to perforin-containing granules for cytotoxicity. BLOOD, 114 19: 4117-4127. doi:10.1182/blood-2009-06-225359


Author Wood, S. M.
Meeths, M
Chiang, S. C. C.
Bechensteen, A. G.
Boelens, J. J.
Heilmann, C
Horiuchi, H
Rosthoj, S
Rutynowska, O
Winiarski, J
Stow, J. L.
Nordenskjold, M
Henter, J. I.
Ljunggren, H. G.
Bryceson, Y. T.
Title Different NK cell-activating receptors preferentially recruit Rab27a or Munc13-4 to perforin-containing granules for cytotoxicity
Journal name BLOOD   Check publisher's open access policy
ISSN 0006-4971
Publication date 2009-11-05
Year available 2009
Sub-type Article (original research)
DOI 10.1182/blood-2009-06-225359
Volume 114
Issue 19
Start page 4117
End page 4127
Total pages 11
Editor Dr. Sanford J. Shattil
Place of publication Washington , DC, U.S.A.
Publisher American Society of Hematology
Collection year 2010
Language eng
Subject C1
970106 Expanding Knowledge in the Biological Sciences
060406 Genetic Immunology
Abstract 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.
Keyword FAMILIAL HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS
GRISCELLI-SYNDROME
IMMUNOLOGICAL SYNAPSE
NATURAL CYTOTOXICITY
SECRETION
EXOCYTOSIS
MUTATIONS
EFFECTOR
IDENTIFICATION
DEGRANULATION
Q-Index Code C1
Q-Index Status Confirmed Code
Additional Notes Prepublished online as a Blood First Edition Paper on August 24, 2009

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2010 Higher Education Research Data Collection
Institute for Molecular Bioscience - Publications
 
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Created: Sun, 22 Nov 2009, 00:08:00 EST