PMID- 26478006
OWN - NLM
STAT- MEDLINE
DCOM- 20160829
LR  - 20191008
IS  - 1097-6825 (Electronic)
IS  - 0091-6749 (Print)
IS  - 0091-6749 (Linking)
VI  - 137
IP  - 4
DP  - 2016 Apr
TI  - Chediak-Higashi syndrome: Lysosomal trafficking regulator domains regulate 
      exocytosis of lytic granules but not cytokine secretion by natural killer cells.
PG  - 1165-1177
LID - S0091-6749(15)01264-6 [pii]
LID - 10.1016/j.jaci.2015.08.039 [doi]
AB  - BACKGROUND: Mutations in lysosomal trafficking regulator (LYST) cause 
      Chediak-Higashi syndrome (CHS), a rare immunodeficiency with impaired cytotoxic 
      lymphocyte function, mainly that of natural killer (NK) cells. Our understanding 
      of NK cell function deficiency in patients with CHS and how LYST regulates lytic 
      granule exocytosis is very limited. OBJECTIVE: We sought to delineate cellular 
      defects associated with LYST mutations responsible for the impaired NK cell 
      function seen in patients with CHS. METHODS: We analyzed NK cells from patients 
      with CHS with missense mutations in the LYST ARM/HEAT (armadillo/huntingtin, 
      elongation factor 3, protein phosphatase 2A, and the yeast kinase TOR1) or BEACH 
      (beige and Chediak-Higashi) domains. RESULTS: NK cells from patients with CHS 
      displayed severely reduced cytotoxicity. Mutations in the ARM/HEAT domain led to 
      a reduced number of perforin-containing granules, which were significantly 
      increased in size but able to polarize to the immunologic synapse; however, they 
      were unable to properly fuse with the plasma membrane. Mutations in the BEACH 
      domain resulted in formation of normal or slightly enlarged granules that had 
      markedly impaired polarization to the IS but could be exocytosed on reaching the 
      immunologic synapse. Perforin-containing granules in NK cells from patients with 
      CHS did not acquire certain lysosomal markers (lysosome-associated membrane 
      protein 1/2) but were positive for markers of transport vesicles 
      (cation-independent mannose 6-phosphate receptor), late endosomes (Ras-associated 
      binding protein 27a), and, to some extent, early endosomes (early endosome 
      antigen 1), indicating a lack of integrity in the endolysosomal compartments. NK 
      cells from patients with CHS had normal cytokine compartments and cytokine 
      secretion. CONCLUSION: LYST is involved in regulation of multiple aspects of NK 
      cell lytic activity, ranging from governance of lytic granule size to control of 
      their polarization and exocytosis, as well as regulation of endolysosomal 
      compartment identity. LYST functions in the regulated exocytosis but not in the 
      constitutive secretion pathway.
CI  - Published by Elsevier Inc.
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 - Wood, Stephanie M
AU  - Wood SM
AD  - Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, 
      Karolinska University Hospital Huddinge, Stockholm, Sweden.
FAU - Murakami, Yousuke
AU  - Murakami Y
AD  - Receptor Cell Biology Section, Laboratory of Immunogenetics, National Institute 
      of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Md.
FAU - Nguyen, Victoria
AU  - Nguyen V
AD  - Receptor Cell Biology Section, Laboratory of Immunogenetics, National Institute 
      of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Md.
FAU - Chiang, Samuel C C
AU  - Chiang SCC
AD  - Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, 
      Karolinska University Hospital Huddinge, Stockholm, Sweden.
FAU - Cullinane, Andrew R
AU  - Cullinane AR
AD  - Office of the Clinical Director, National Human Genome Research Institute, 
      National Institutes of Health, Bethesda, Md.
FAU - Peruzzi, Giovanna
AU  - Peruzzi G
AD  - Receptor Cell Biology Section, Laboratory of Immunogenetics, National Institute 
      of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Md.
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 - 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 - Introne, Wendy J
AU  - Introne WJ
AD  - Office of the Clinical Director, National Human Genome Research Institute, 
      National Institutes of Health, Bethesda, Md.
FAU - Bryceson, Yenan T
AU  - Bryceson YT
AD  - Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, 
      Karolinska University Hospital Huddinge, Stockholm, Sweden.
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/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20151021
PL  - United States
TA  - J Allergy Clin Immunol
JT  - The Journal of allergy and clinical immunology
JID - 1275002
RN  - 0 (Cytokines)
RN  - 0 (Genetic Markers)
RN  - 0 (LYST protein, human)
RN  - 0 (Vesicular Transport Proteins)
SB  - IM
MH  - Adult
MH  - Chediak-Higashi Syndrome/genetics/*physiopathology
MH  - Cytokines/*metabolism
MH  - Exocytosis/*physiology
MH  - Female
MH  - Genetic Markers
MH  - Humans
MH  - Killer Cells, Natural/*metabolism
MH  - Lysosomes/*physiology
MH  - Male
MH  - Mutation, Missense
MH  - Vesicular Transport Proteins/*genetics/physiology
PMC - PMC4826811
MID - NIHMS731241
OTO - NOTNLM
OT  - Chediak-Higashi syndrome
OT  - cytotoxic lymphocyte
OT  - cytotoxicity
OT  - exocytosis
OT  - immune deficiency
OT  - lysosomal trafficking regulator
OT  - lysosomes
OT  - lytic granules
OT  - natural killer cell
EDAT- 2015/10/20 06:00
MHDA- 2016/08/30 06:00
PMCR- 2017/04/01
CRDT- 2015/10/20 06:00
PHST- 2015/04/22 00:00 [received]
PHST- 2015/07/27 00:00 [revised]
PHST- 2015/08/24 00:00 [accepted]
PHST- 2015/10/20 06:00 [entrez]
PHST- 2015/10/20 06:00 [pubmed]
PHST- 2016/08/30 06:00 [medline]
PHST- 2017/04/01 00:00 [pmc-release]
AID - S0091-6749(15)01264-6 [pii]
AID - 10.1016/j.jaci.2015.08.039 [doi]
PST - ppublish
SO  - J Allergy Clin Immunol. 2016 Apr;137(4):1165-1177. doi: 
      10.1016/j.jaci.2015.08.039. Epub 2015 Oct 21.