Positive and negative phosphorylation regulates RIP1- and RIP3-induced programmed necrosis.
Biochem J
; 456(3): 409-15, 2013 Dec 15.
Article
em En
| MEDLINE
| ID: mdl-24059293
ABSTRACT
Programmed necrosis or necroptosis is controlled by the action of two serine/threonine kinases, RIP1 (receptor-interacting serine/threonine protein kinase 1; also known as RIPK1) and RIP3. The phosphorylation of RIP1 and RIP3 is critical for assembly of the necrosome, an amyloid-like complex that initiates transmission of the pro-necrotic signal. In the present study, we used site-directed mutagenesis to systematically examine the effects of putative phosphoacceptor sites on RIP1 and RIP3 on TNF (tumour necrosis factor)-induced programmed necrosis. We found that mutation of individual serine residues in the kinase domain of RIP1 had little effect on RIP1 kinase activity and TNF-induced programmed necrosis. Surprisingly, an alanine residue substitution for Ser(89) enhanced RIP1 kinase activity and TNF-induced programmed necrosis without affecting RIP1-RIP3 necrosome formation. This indicates that Ser(89) is an inhibitory phosphoacceptor site that can dampen the pro-necrotic function of RIP1. In addition, we show that a phosphomimetic mutant of RIP3, S204D, led to programmed necrosis that was refractory to RIP1 siRNA and insensitive to necrostatin-1 inhibition. Our results show that programmed necrosis is regulated by positive and inhibitory phosphorylation events.
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Ligação a RNA
/
Substituição de Aminoácidos
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Mutação de Sentido Incorreto
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Complexo de Proteínas Formadoras de Poros Nucleares
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Proteína Serina-Treonina Quinases de Interação com Receptores
Limite:
Humans
Idioma:
En
Revista:
Biochem J
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos