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Filamin (280-kDa actin-binding protein) is a caspase substrate and Is also cleaved directly by the cytotoxic T lymphocyte protease granzyme B during apoptosis

Browne, Kylie; Johnstone, Rufus A; Jans, David A; Trapani, Joseph A

Description

We used yeast two-hybrid screening to identify the cytoskeletal protein filamin as a ligand for the proapoptotic protease granzyme B, produced by cytotoxic T lymphocytes. Filamin was directly cleaved by granzyme B when target cells were exposed to granzyme B and the lytic protein perforin, but it was also cleaved in a caspase-dependent manner following the ligation of Fas receptors. A similar pattern of filamin cleavage to polypeptides of ∼110 and 95 kDa was observed in Jurkat cells killed by...[Show more]

dc.contributor.authorBrowne, Kylie
dc.contributor.authorJohnstone, Rufus A
dc.contributor.authorJans, David A
dc.contributor.authorTrapani, Joseph A
dc.date.accessioned2015-12-13T23:16:39Z
dc.identifier.issn0021-9258
dc.identifier.urihttp://hdl.handle.net/1885/89517
dc.description.abstractWe used yeast two-hybrid screening to identify the cytoskeletal protein filamin as a ligand for the proapoptotic protease granzyme B, produced by cytotoxic T lymphocytes. Filamin was directly cleaved by granzyme B when target cells were exposed to granzyme B and the lytic protein perforin, but it was also cleaved in a caspase-dependent manner following the ligation of Fas receptors. A similar pattern of filamin cleavage to polypeptides of ∼110 and 95 kDa was observed in Jurkat cells killed by either mechanism. However, filamin cleavage in response to granzyme B was not inhibited by the caspase inhibitor z-Val-Ala-Asp-fluoromethylketone at concentrations that abolished DNA fragmentation. Filamin staining was redistributed from the cell membrane into the cytoplasm of Jurkat cells exposed to granzyme B and perforin and following ligation of Fas receptors, coincident with the morphological changes of apoptosis. Filamin-deficient human melanoma cells were significantly (although not completely) protected from granzyme B-mediated death compared with isogenic filamin-expressing cells, both in clonogenic survival and 51Cr release assays, whereas death from multiple other stimuli was not affected by filamin deficiency. Thus, filamin is a functionally important substrate for granzyme B, as its cleavage may account at least partly for caspase-independent cell death mediated by the granzyme.
dc.publisherAmerican Society for Biochemistry and Molecular Biology Inc
dc.sourceJournal of Biological Chemistry
dc.subjectKeywords: actin binding protein; caspase; caspase inhibitor; DNA fragment; Fas antigen; filamin; granzyme B; ketone derivative; lymphocyte antigen receptor; perforin; polypeptide; proteinase; apoptosis; article; controlled study; cytotoxic T lymphocyte; enzyme acti
dc.titleFilamin (280-kDa actin-binding protein) is a caspase substrate and Is also cleaved directly by the cytotoxic T lymphocyte protease granzyme B during apoptosis
dc.typeJournal article
local.description.notesImported from ARIES
local.description.refereedYes
local.identifier.citationvolume275
dc.date.issued2000
local.identifier.absfor060103 - Cell Development, Proliferation and Death
local.identifier.ariespublicationMigratedxPub19574
local.type.statusPublished Version
local.contributor.affiliationBrowne, Kylie, Peter MacCallum Cancer Centre
local.contributor.affiliationJohnstone, Rufus A, University of Cambridge
local.contributor.affiliationJans, David A, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationTrapani, Joseph A, Peter MacCallum Cancer Centre
local.description.embargo2037-12-31
local.bibliographicCitation.issue50
local.bibliographicCitation.startpage39262
local.bibliographicCitation.lastpage39266
local.identifier.doi10.1074/jbc.C000622200
dc.date.updated2015-12-12T08:49:05Z
local.identifier.scopusID2-s2.0-0034671856
CollectionsANU Research Publications

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