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Targeting proteins to secretory lysosomes of natural killer cells as a principle for immunoregulation.

Hansson, Markus LU ; Jönsson, Sofia LU ; Persson, Ann-Maj LU ; Calafat, Jero; Tapper, Hans LU and Olsson, Inge LU (2003) In Molecular Immunology 40(6). p.363-372
Abstract
Secretory lysosomes of natural killer (NK) cells combine storage, regulated secretion and lysosomal activity. We asked whether one could target exogenous proteins to the secretory lysosomes of NK-cells for final delivery into a tumor site upon degranulation. cDNAs for both soluble and transmembrane (tm) proteins were expressed in the human YT-Indy NK-cell line. Targeting of a soluble TNF receptor (sTNFR1) was achieved by expressing a cDNA construct with a transmembrane sequence to facilitate ER-export and by incorporating a cytosolic sorting signal (Y) from CD63 to overcome constitutive secretion. The resulting sTNFR1-tm-Y was targeted to secretory lysosomes as confirmed by results from biosynthetic radiolabeling in combination with... (More)
Secretory lysosomes of natural killer (NK) cells combine storage, regulated secretion and lysosomal activity. We asked whether one could target exogenous proteins to the secretory lysosomes of NK-cells for final delivery into a tumor site upon degranulation. cDNAs for both soluble and transmembrane (tm) proteins were expressed in the human YT-Indy NK-cell line. Targeting of a soluble TNF receptor (sTNFR1) was achieved by expressing a cDNA construct with a transmembrane sequence to facilitate ER-export and by incorporating a cytosolic sorting signal (Y) from CD63 to overcome constitutive secretion. The resulting sTNFR1-tm-Y was targeted to secretory lysosomes as confirmed by results from biosynthetic radiolabeling in combination with subcellular fractionation, immunoelectron microscopy, and immunofluorescence microscopy. A soluble sTNFR1 form was generated in the secretory lysosome by endogenous proteolytic activity. Expression of exogenous normally secretory non-membrane proteins, such as alpha1-microglobulin (alpha1-m) and alpha1-antitrypsin (alpha1-at) resulted mostly in constitutive secretion although a small amount of alpha1-microglobulin was targeted to secretory lysosomes. Our results suggest a potential for delivery of pharmacologically active agents into tumor sites by use of the NK-cell secretory lysosome as a carrier. (C) 2003 Elsevier Ltd. All rights reserved. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Immunology
volume
40
issue
6
pages
363 - 372
publisher
Pergamon
external identifiers
  • wos:000185843000006
  • scopus:0141533219
ISSN
1872-9142
DOI
10.1016/S0161-5890(03)00151-2
language
English
LU publication?
yes
id
9e6ef65e-280f-480c-95c2-8ec585bac8f7 (old id 118352)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14522017&dopt=Abstract
date added to LUP
2007-07-04 16:14:50
date last changed
2018-10-03 11:12:48
@article{9e6ef65e-280f-480c-95c2-8ec585bac8f7,
  abstract     = {Secretory lysosomes of natural killer (NK) cells combine storage, regulated secretion and lysosomal activity. We asked whether one could target exogenous proteins to the secretory lysosomes of NK-cells for final delivery into a tumor site upon degranulation. cDNAs for both soluble and transmembrane (tm) proteins were expressed in the human YT-Indy NK-cell line. Targeting of a soluble TNF receptor (sTNFR1) was achieved by expressing a cDNA construct with a transmembrane sequence to facilitate ER-export and by incorporating a cytosolic sorting signal (Y) from CD63 to overcome constitutive secretion. The resulting sTNFR1-tm-Y was targeted to secretory lysosomes as confirmed by results from biosynthetic radiolabeling in combination with subcellular fractionation, immunoelectron microscopy, and immunofluorescence microscopy. A soluble sTNFR1 form was generated in the secretory lysosome by endogenous proteolytic activity. Expression of exogenous normally secretory non-membrane proteins, such as alpha1-microglobulin (alpha1-m) and alpha1-antitrypsin (alpha1-at) resulted mostly in constitutive secretion although a small amount of alpha1-microglobulin was targeted to secretory lysosomes. Our results suggest a potential for delivery of pharmacologically active agents into tumor sites by use of the NK-cell secretory lysosome as a carrier. (C) 2003 Elsevier Ltd. All rights reserved.},
  author       = {Hansson, Markus and Jönsson, Sofia and Persson, Ann-Maj and Calafat, Jero and Tapper, Hans and Olsson, Inge},
  issn         = {1872-9142},
  language     = {eng},
  number       = {6},
  pages        = {363--372},
  publisher    = {Pergamon},
  series       = {Molecular Immunology},
  title        = {Targeting proteins to secretory lysosomes of natural killer cells as a principle for immunoregulation.},
  url          = {http://dx.doi.org/10.1016/S0161-5890(03)00151-2},
  volume       = {40},
  year         = {2003},
}