A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes.
Interleukin-1 beta (IL-1 beta)-converting enzyme cleaves the IL-1 beta precursor to mature IL-1 beta, an important mediator of inflammation. The identification of the enzyme as a unique cysteine protease and the design of potent peptide aldehyde inhibitors are described. Purification and cloning of the complementary DNA indicates that IL-1 beta-converting enzyme is composed of two nonidentical subunits that are derived from a single proenzyme, possibly by autoproteolysis. Selective inhibition of the enzyme in human blood monocytes blocks production of mature IL-1 beta, indicating that it is a potential therapeutic target.
Thornberry
N A
NA
Department of Biochemistry, Merck Research Laboratories, Rahway, New Jersey 07065.
Bull
H G
HG
Calaycay
J R
JR
Chapman
K T
KT
Howard
A D
AD
Kostura
M J
MJ
Miller
D K
DK
Molineaux
S M
SM
Weidner
J R
JR
Aunins
J
J
D000595:Amino Acid Sequence; D001483:Base Sequence; D001667:Binding, Competitive / Q000187:drug effects; D020170:Caspase 1; D002846:Chromatography, Affinity; D002848:Chromatography, DEAE-Cellulose; D002851:Chromatography, High Pressure Liquid; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D003978:Diazomethane / Q000031:analogs & derivatives / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D008969:Molecular Sequence Data; D009000:Monocytes / Q000201:enzymology*; D016366:Open Reading Frames; D011499:Protein Processing, Post-Translational; D012689:Sequence Homology, Nucleic Acid; D013379:Substrate Specificity
D007375:Interleukin-1; C015795:diazomethyl ketones; D003978:Diazomethane; D020170:Caspase 1; D008666:Metalloendopeptidases