The familial Mediterranean fever protein, pyrin, is cleaved by caspase-1 and activates NF-kappaB through its N-terminal fragment.
Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by mutations in MEFV, which encodes a 781-amino acid protein denoted pyrin. We have previously shown that pyrin regulates caspase-1 activation and IL-1beta production through interaction of its N-terminal PYD motif with the ASC adapter protein, and also modulates IL-1beta production by interaction of its C-terminal B30.2 domain with the catalytic domains of caspase-1. We now asked whether pyrin might itself be a caspase-1 substrate, and found that pyrin is cleaved by caspase-1 at Asp330, a site remote from the B30.2 domain. Pyrin variants harboring FMF-associated B30.2 mutations were cleaved more efficiently than wild-type pyrin. The N-terminal cleaved fragment interacted with the p65 subunit of NF-kappaB and with IkappaB-alpha through its 15-aa bZIP basic domain and adjacent sequences, respectively, and translocated to the nucleus. The interaction of the N-terminal fragment with p65 enhanced entrance of p65 into the nucleus. The interaction of N-terminal pyrin with IkappaB-alpha induced calpain-mediated degradation of IkappaB-alpha, thus potentiating NF-kappaB activation. Absolute and relative quantities of cleaved pyrin and IkappaB-alpha degradation products were substantially increased in leukocytes from FMF patients compared with healthy controls. Our data support a new pyrin/caspase-1 pathway for NF-kappaB activation.
Chae
Jae Jin
JJ
Genetics and Genomics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD 20892-1820, USA. chaej@exchange.nih.gov
Wood
Geryl
G
Richard
Katharina
K
Jaffe
Howard
H
Colburn
Nona T
NT
Masters
Seth L
SL
Gumucio
Deborah L
DL
Shoham
Nitza G
NG
Kastner
Daniel L
DL
D001665:Binding Sites / Q000235:genetics; D002154:Calpain / Q000037:antagonists & inhibitors; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003078:Colchicine / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010505:Familial Mediterranean Fever / Q000235:genetics / Q000378:metabolism*; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D000071198:Pyrin; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D051996:Transcription Factor RelA / Q000378:metabolism; D014162:Transfection
D003598:Cytoskeletal Proteins; D020672:I-kappa B Proteins; C000604192:MEFV protein, human; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D010446:Peptide Fragments; D000071198:Pyrin; D011994:Recombinant Proteins; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D002154:Calpain; D020170:Caspase 1; D003078:Colchicine