PMID- 29241728
OWN - NLM
STAT- MEDLINE
DCOM- 20191014
LR  - 20191014
IS  - 1097-6825 (Electronic)
IS  - 0091-6749 (Print)
IS  - 0091-6749 (Linking)
VI  - 142
IP  - 3
DP  - 2018 Sep
TI  - An actin cytoskeletal barrier inhibits lytic granule release from natural killer 
      cells in patients with Chediak-Higashi syndrome.
PG  - 914-927.e6
LID - S0091-6749(17)31887-0 [pii]
LID - 10.1016/j.jaci.2017.10.040 [doi]
AB  - BACKGROUND: Chediak-Higashi syndrome (CHS) is a rare disorder caused by biallelic 
      mutations in the lysosomal trafficking regulator gene (LYST), resulting in 
      formation of giant lysosomes or lysosome-related organelles in several cell 
      types. The disease is characterized by immunodeficiency and a fatal 
      hemophagocytic lymphohistiocytosis caused by impaired function of cytotoxic 
      lymphocytes, including natural killer (NK) cells. OBJECTIVE: We sought to 
      determine the underlying biochemical cause of the impaired cytotoxicity of NK 
      cells in patients with CHS. METHODS: We generated a human cell model of CHS using 
      Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology. We 
      used a combination of classical techniques to evaluate lysosomal function and 
      cell activity in the model system and super-resolution microscopy to visualize 
      F-actin and lytic granules in normal and LYST-deficient NK cells. RESULTS: Loss 
      of LYST function in a human NK cell line, NK92mi, resulted in inhibition of NK 
      cell cytotoxicity and reproduced other aspects of the CHS cellular phenotype, 
      including the presence of significantly enlarged lytic granules with defective 
      exocytosis and impaired integrity of endolysosomal compartments. The large 
      granules had an acidic pH and normal activity of lysosomal enzymes and were 
      positive for the proteins essential for lytic granule exocytosis. Visualization 
      of the actin meshwork openings at the immunologic synapse revealed that the 
      cortical actin acts as a barrier for secretion of such large granules at the 
      cell-cell contact site. Decreasing the cortical actin density at the immunologic 
      synapse or decreasing the lytic granule size restored the ability of 
      LYST-deficient NK cells to degranulate and kill target cells. CONCLUSION: The 
      cortical actin and granule size play significant roles in NK cell cytotoxic 
      function. We present evidence that the periodicity of subsynaptic actin is an 
      important factor limiting the release of large lytic granules from NK cells from 
      patients with CHS and could be a novel target for pharmaceutical intervention.
CI  - Copyright (c) 2018 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Gil-Krzewska, Aleksandra
AU  - Gil-Krzewska A
AD  - Receptor Cell Biology Section, Laboratory of Immunogenetics, National Institute 
      of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD.
FAU - Saeed, Mezida B
AU  - Saeed MB
AD  - Manchester Collaborative Centre for Inflammation Research, University of 
      Manchester, Manchester, United Kingdom.
FAU - Oszmiana, Anna
AU  - Oszmiana A
AD  - Manchester Collaborative Centre for Inflammation Research, University of 
      Manchester, Manchester, United Kingdom.
FAU - Fischer, Elizabeth R
AU  - Fischer ER
AD  - Electron Microscopy Unit, Research Technologies Branch, Rocky Mountain 
      Laboratories, National Institute of Allergy and Infectious Diseases, National 
      Institutes of Health, Hamilton, Mont.
FAU - Lagrue, Kathryn
AU  - Lagrue K
AD  - Manchester Collaborative Centre for Inflammation Research, University of 
      Manchester, Manchester, United Kingdom.
FAU - Gahl, William A
AU  - Gahl WA
AD  - Office of the Clinical Director, National Human Genome Research Institute, 
      National Institutes of Health, Bethesda, MD.
FAU - Introne, Wendy J
AU  - Introne WJ
AD  - Office of the Clinical Director, National Human Genome Research Institute, 
      National Institutes of Health, Bethesda, MD.
FAU - Coligan, John E
AU  - Coligan JE
AD  - Receptor Cell Biology Section, Laboratory of Immunogenetics, National Institute 
      of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD.
FAU - Davis, Daniel M
AU  - Davis DM
AD  - Manchester Collaborative Centre for Inflammation Research, University of 
      Manchester, Manchester, United Kingdom.
FAU - Krzewski, Konrad
AU  - Krzewski K
AD  - Receptor Cell Biology Section, Laboratory of Immunogenetics, National Institute 
      of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD. 
      Electronic address: krzewskikj@niaid.nih.gov.
LA  - eng
GR  - Z99 AI999999/NULL/International
GR  - ZIA AI000962-11/NULL/International
GR  - 110091/WT_/Wellcome Trust/United Kingdom
GR  - Z99 AI999999/Intramural NIH HHS/United States
GR  - G1001044/MRC_/Medical Research Council/United Kingdom
GR  - ZIA AI000962-11/Intramural NIH HHS/United States
GR  - Wellcome Trust/United Kingdom
GR  - ZIA AI001174-05/NULL/International
GR  - ZIA AI001174-05/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Observational Study
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20171211
PL  - United States
TA  - J Allergy Clin Immunol
JT  - The Journal of allergy and clinical immunology
JID - 1275002
RN  - 0 (Actins)
RN  - 0 (LYST protein, human)
RN  - 0 (Vesicular Transport Proteins)
SB  - IM
MH  - Actins/*immunology
MH  - Cell Line
MH  - Chediak-Higashi Syndrome/*immunology
MH  - Cytoplasmic Granules/*immunology
MH  - Cytoskeleton/immunology
MH  - Humans
MH  - Killer Cells, Natural/*immunology
MH  - Vesicular Transport Proteins/genetics
PMC - PMC5995607
MID - NIHMS926643
OTO - NOTNLM
OT  - Chediak-Higashi syndrome
OT  - actin cytoskeleton
OT  - cytotoxic lymphocyte
OT  - cytotoxicity
OT  - exocytosis
OT  - immune deficiency
OT  - lysosomal trafficking regulator
OT  - lysosomes
OT  - lytic granules
OT  - natural killer cell
EDAT- 2017/12/16 06:00
MHDA- 2019/10/15 06:00
PMCR- 2018/09/01
CRDT- 2017/12/16 06:00
PHST- 2017/03/07 00:00 [received]
PHST- 2017/09/21 00:00 [revised]
PHST- 2017/10/26 00:00 [accepted]
PHST- 2017/12/16 06:00 [pubmed]
PHST- 2019/10/15 06:00 [medline]
PHST- 2017/12/16 06:00 [entrez]
PHST- 2018/09/01 00:00 [pmc-release]
AID - S0091-6749(17)31887-0 [pii]
AID - 10.1016/j.jaci.2017.10.040 [doi]
PST - ppublish
SO  - J Allergy Clin Immunol. 2018 Sep;142(3):914-927.e6. doi: 
      10.1016/j.jaci.2017.10.040. Epub 2017 Dec 11.