Protein Phosphatase 2A and Neutral Sphingomyelinase 2 Regulate IRAK-1 Protein Ubiquitination and Degradation in Response to Interleukin-1β
Protein Phosphatase 2A and Neutral Sphingomyelinase 2 Regulate IRAK-1 Protein Ubiquitination and Degradation in Response to Interleukin-1β
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DOI：
10.1074/jbc.m111.238030
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发表时间：
2011-09-16
影响因子：
4.8
通讯作者：
Nikolova-Karakashian, Mariana N.
中科院分区：
文献类型：
--
作者：
Dobierzewska, Aneta;Giltiay, Natalia V.;Nikolova-Karakashian, Mariana N.
The IL-1 beta signaling cascade is initiated by the phosphorylation of IL-1 beta receptor-associated kinase-1 (IRAK-1), followed by its ubiquitination and degradation. This paper investigates the regulation of IRAK-1 degradation in primary hepatocytes and in HEK cells overexpressing the IL-1 beta receptor. We provide evidence that protein phosphatase 2A (PP2A) is a negative regulator of the phosphorylation, Lys(48)-linked ubiquitination, and degradation of IRAK-1. PP2A catalytic activity increased within 30 min of stimulation with IL-1 beta. siRNA against PP2A catalytic subunit (PP2Ac) or treatment with pharmacological inhibitor, okadaic acid, enhanced IRAK-1 Lys(48)-linked ubiquitination and degradation. Direct interaction between PP2Ac and IRAK-1 was observed, suggesting that IRAK-1 might be a PP2A substrate. The mechanisms of PP2A activation by IL-1 beta involved neutral sphingomyelinase-2 (NSMase-2) and an accumulation of ceramide. Overexpression of NSMase-2 delayed IRAK-1 degradation in a PP2A-dependent manner, whereas NSMase-2 silencing had the opposite effect. The addition of sphingomyelinase, ceramide, or a proteasome inhibitor all led to retention of IRAK-1 at the cell membrane and to increased JNK phosphorylation. This study suggests that NSMase-2- and PP2A-dependent regulation of IRAK-1 degradation is a novel mechanism to fine tune the magnitude of IL-1 beta response.
