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Perforin oligomers form arcs in cellular membranes: a locus for intracellular delivery of granzymes
- Source :
- Cell death and differentiation (Online) 22 (2015): 74–85. doi:10.1038/cdd.2014.110, info:cnr-pdr/source/autori:Metkar S.S.; Marchioretto M.; Antonini V.; Lunelli L.; Wang B.; Gilbert R.J.; Anderluh G.; Roth R.; Pooga M.; Pardo J.; Heuser J.E.; Dalla Serra M.; Froelich C.J./titolo:Perforin oligomers form arcs in cellular membranes: a locus for intracellular delivery of granzymes/doi:10.1038%2Fcdd.2014.110/rivista:Cell death and differentiation (Online)/anno:2015/pagina_da:74/pagina_a:85/intervallo_pagine:74–85/volume:22
- Publication Year :
- 2014
- Publisher :
- Nature Publishing Group, 2014.
-
Abstract
- Perforin-mediated cytotoxicity is an essential host defense, in which defects contribute to tumor development and pathogenic disorders including autoimmunity and autoinflammation. How perforin (PFN) facilitates intracellular delivery of pro-apoptotic and inflammatory granzymes across the bilayer of targets remains unresolved. Here we show that cellular susceptibility to granzyme B (GzmB) correlates with rapid PFN-induced phosphatidylserine externalization, suggesting that pores are formed at a protein-lipid interface by incomplete membrane oligomers (or arcs). Supporting a role for these oligomers in protease delivery, an anti-PFN antibody (pf-80) suppresses necrosis but increases phosphatidylserine flip-flop and GzmB-induced apoptosis. As shown by atomic force microscopy on planar bilayers and deep-etch electron microscopy on mammalian cells, pf-80 increases the proportion of arcs which correlates with the presence of smaller electrical conductances, while large cylindrical pores decline. PFN appears to form arc structures on target membranes that serve as minimally disrupting conduits for GzmB translocation. The role of these arcs in PFN-mediated pathology warrants evaluation where they may serve as novel therapeutic targets.Cell Death and Differentiation advance online publication, 22 August 2014; doi:10.1038/cdd.2014.110.
- Subjects :
- Cell Membrane Permeability
Apoptosis
GRANULE-MEDIATED APOPTOSIS
PLASMA-MEMBRANE
PORE FORMATION
TARGET-CELLS
PENETRATING PEPTIDES
Granzymes
GZMB
Cell membrane
chemistry.chemical_compound
Jurkat Cells
Necrosis
medicine
Humans
Molecular Biology
Original Paper
biology
Perforin
Cell Membrane
Cell Biology
Phosphatidylserine
Antibodies, Neutralizing
Cell biology
Transport protein
Granzyme B
Protein Transport
medicine.anatomical_structure
chemistry
Granzyme
Multiprotein Complexes
biology.protein
Intracellular
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Cell death and differentiation (Online) 22 (2015): 74–85. doi:10.1038/cdd.2014.110, info:cnr-pdr/source/autori:Metkar S.S.; Marchioretto M.; Antonini V.; Lunelli L.; Wang B.; Gilbert R.J.; Anderluh G.; Roth R.; Pooga M.; Pardo J.; Heuser J.E.; Dalla Serra M.; Froelich C.J./titolo:Perforin oligomers form arcs in cellular membranes: a locus for intracellular delivery of granzymes/doi:10.1038%2Fcdd.2014.110/rivista:Cell death and differentiation (Online)/anno:2015/pagina_da:74/pagina_a:85/intervallo_pagine:74–85/volume:22
- Accession number :
- edsair.doi.dedup.....1e4995c08e7406a5f697757e94912ef7
- Full Text :
- https://doi.org/10.1038/cdd.2014.110