Current knowledge on procaspase-1 variants with reduced or abrogated enzymatic activity in autoinflammatory disease.
Curr Rheumatol Rep
; 17(7): 45, 2015 Jul.
Article
em En
| MEDLINE
| ID: mdl-26003867
ABSTRACT
Caspase-1 is a proinflammatory enzyme that is essential in many inflammatory conditions including infectious, autoimmune, and autoinflammatory disorders. The inflammation is mainly mediated by the generation of inflammasomes that activate caspase-1 and subsequently interleukin (IL)-1ß and IL-18. In addition, homotypic CARD/CARD interaction of procaspase-1 with RIP2 and thereby activation of the NF-κB pathways may play some role in the inflammation. However, normally, this pathway seems to become downregulated rapidly by the cleavage and excretion of RIP2 by active (pro-)caspase-1. In patients with unexplained recurrent systemic inflammation, CASP1 variants were detected, which often destabilized the caspase-1 dimer interface. Obviously, the resulting decreased or abrogated enzymatic activity and IL-1ß production did not prevent the febrile episodes. As an unexpected finding, the inactive procaspase-1 variants significantly enhanced proinflammatory signaling by increasing RIP2 mediated NF-κB activation in an in vitro cell transfection model. A likely reason is the failure of inactive procaspase-1 to cleave bound RIP2 and also to mediate its excretion out of the intracelluar space thereby keeping the RIP2-NF-κB pathway upregulated. Hence, proinflammatory effects of enzymatically inactive procaspase-1 variants may partially explain the inflammatory episodes of the patients.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doenças Autoimunes
/
Caspase 1
/
Febre
/
Inflamação
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Curr Rheumatol Rep
Assunto da revista:
REUMATOLOGIA
Ano de publicação:
2015
Tipo de documento:
Article