A metalloprotease inhibitor blocks shedding of the 80-kD TNF receptor and TNF processing in T lymphocytes.
1995
TNF is synthesized as a 26-kD membrane-anchored precursor and is proteolytically
processed at the cell surface to yield the mature secreted 17-kD polypeptide.
The 80-kD tumor necrosis factor (TNF) receptor (TNFR80) is also proteolytically
cleaved at the cell surface (shed), releasing a soluble ligand-binding receptor
fragment. Since processing of TNF and TNFR80 occurs concurrently in activated T
cells, we asked whether a common protease may be involved. Here, we present
evidence that a recently described inhibitor of TNF processing
N-(D,L-[2-(hydroxyaminocarbonyl)methyl]-4-methylpentanoyl)L- 3-(29naphthyl)-
alanyl-L-alanine, 2-aminoethyl amide (TAPI) also blocks shedding of TNFR80,
suggesting that these processes may be coordinately regulated during T cell
activation. In addition, studies of murine fibroblasts transfected with human
TNFR80, or a cytoplasmic deletion form of TNFR80, reveal that inhibition of
TNFR80 shedding by TAPI is independent of receptor phosphorylation and does not
require the receptor cytoplasmic domain.
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