INCA, a novel human caspase recruitment domain protein that inhibits interleukin-1beta generation.
Using in silico methods for screening the human genome for new caspase recruitment domain (CARD) proteins, we have identified INCA (Inhibitory CARD) as a protein that shares 81% identity with the prodomain of caspase-1. The INCA gene is located on chromosome 11q22 between the genes of COP/Pseudo-ICE and ICEBERG, two other CARD proteins that arose from caspase-1 gene duplications. We show that INCA mRNA is expressed in many tissues. INCA is specifically upregulated by interferon-gamma in the monocytic cell lines THP-1 and U937. INCA physically interacts with procaspase-1 and blocks the release of mature IL-1beta from LPS-stimulated macrophages. Unlike COP/Pseudo-ICE and procaspase-1, INCA does not interact with RIP2 and does not induce NF-kappaB activation. Our data show that INCA is a novel intracellular regulator of procaspase-1 activation, involved in the regulation of pro-IL-1beta processing and its release during inflammation.
Lamkanfi
Mohamed
M
Unit of Molecular Signalling and Cell Death, Department for Molecular Biomedical Research, VIB-Ghent University, Technologiepark 927, Zwijnaarde B-9052, Belgium.
Denecker
Geertrui
G
Kalai
Michael
M
D'hondt
Kathleen
K
Meeus
Ann
A
Declercq
Wim
W
Saelens
Xavier
X
Vandenabeele
Peter
P
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D020170:Caspase 1; D020169:Caspases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D004792:Enzyme Precursors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000096:biosynthesis*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014018:Tissue Distribution; D020298:U937 Cells; D015854:Up-Regulation / Q000187:drug effects
D048868:Adaptor Proteins, Signal Transducing; C495731:CARD17 protein, human; D002352:Carrier Proteins; D018076:DNA, Complementary; D004792:Enzyme Precursors; D007375:Interleukin-1; D016328:NF-kappa B; D012333:RNA, Messenger; D011994:Recombinant Proteins; D007371:Interferon-gamma; D020169:Caspases; D020170:Caspase 1