Disease-associated mutations in CIAS1 induce cathepsin B-dependent rapid cell death of human THP-1 monocytic cells.
Mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene are associated with a spectrum of autoinflammatory diseases, including familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurologic, cutaneous, articular syndrome, also known as neonatal-onset multisystem inflammatory disease. CIAS1 encodes cryopyrin, a protein that localizes to the cytosol and functions as pattern recognition receptor. Cryopyrin also participates in nuclear factor-kappaB regulation and caspase-1-mediated maturation of interleukin 10. In this study, we showed that disease-associated mutations in CIAS1 induced rapid cell death of THP-1 monocytic cells. The features of cell death, including 7-AAD staining, the presence of cellular edema, and early membrane damage resulting in lactate dehydrogenase (LDH) release, indicated that it was more likely to be necrosis than apoptosis, and was effectively blocked with the cathepsin B-specific inhibitor CA-074-Me. CA-074-Me also suppressed induced by disease-associated mutation lysosomal leakage and mitochondrial damage. In addition, R837, a recently identified activator of cryopyrin-associated inflammasomes, induced cell death in wild type CIAS1-transfected THP-1 cells. These results indicated that monocytes undergo rapid cell death in a cathepsin B-dependent manner upon activation of cryopyrin, which is also a specific phenomenon induced by disease-associated mutation of CIAS1.
Fujisawa
Akihiro
A
Department of Dermatology, Kyoto University Graduate School of Medicine, Japan.
Kambe
Naotomo
N
Saito
Megumu
M
Nishikomori
Ryuta
R
Tanizaki
Hideaki
H
Kanazawa
Nobuo
N
Adachi
Souichi
S
Heike
Toshio
T
Sagara
Junji
J
Suda
Takashi
T
Nakahata
Tatsutoshi
T
Miyachi
Yoshiki
Y
D019943:Amino Acid Substitution; D000634:Aminoquinolines / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology*; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D004151:Dipeptides / Q000494:pharmacology; D006801:Humans; D000077271:Imiquimod; D007249:Inflammation / Q000209:etiology / Q000235:genetics / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009336:Necrosis; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D000634:Aminoquinolines; C400541:CA 074 methyl ester; D002352:Carrier Proteins; D004151:Dipeptides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D011994:Recombinant Proteins; D002401:Cathepsin B; D000077271:Imiquimod