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首页> 外文期刊>Cellular Signalling >Cyclic GMP specifically suppresses Type-I alpha cGMP-dependent protein kinase expression by ubiquitination
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Cyclic GMP specifically suppresses Type-I alpha cGMP-dependent protein kinase expression by ubiquitination

机译：环状GMP通过泛素化特异性抑制I型αcGMP依赖性蛋白激酶表达

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摘要

Type I cGMP-dependent protein kinase (PKG-I) mediates nitric oxide (NO) and hormone dependent smooth muscle relaxation and stimulates smooth muscle cell-specific gene expression. Expression of PKG-I in cultured smooth muscle cells depends on culture conditions and is inhibited by inflammatory cytokines such as interleukin-I and tumor necrosis factor-alpha, which are known to stimulate Type II NO synthase (iNOS) expression. We report here that the suppression of PKG-I protein levels in smooth muscle cells is triggered by the ubiquitin/26S proteasome pathway. Incubation of vascular smooth muscle cells with phosphodiesterase-resistant cyclic GMP analogs (e.g., 8-bromo-cGMP) decreases PKG-I protein level in a time- and concentration-dependent manner. To study this process, we tested the effects of 8-Br-cGMP on PKG-I protein level in Cos7 cells, which do not express endogenous type I PKG mRNA. 8-Br-cGMP induced the ubiquitination and down-regulation of PKG-I alpha, but not PKG-I beta. Treatment of cells with the 26S proteasome inhibitor, MG-132, increased ubiquitination of PKG. Blocking PKG-I catalytic activity using the cell-permeant specific PKG-I inhibitor, DT-2, inhibited cGMP-induced PKG-I ubiquitination and down-regulation, suggesting that PKG catalytic activity and autophosphorylation were required for suppression of PKG-I level. Mutation of the known autophosphorylation sites of PKG-I alpha to alanine uncovered a specific role for autophosphorylation of serine-64 in cGMP-dependent ubiquitination and suppression of PKG-I level. The results suggest that chronic elevation of cGMP, as seen in inflammatory conditions, triggers ubiquitination and degradation of PKG-I alpha in smooth muscle.
机译：I型cGMP依赖性蛋白激酶（PKG-1）介导一氧化氮（NO）和激素依赖性平滑肌松弛，并刺激平滑肌细胞特异性基因表达。 PKG-I在培养的平滑肌细胞中的表达取决于培养条件，并受到炎症性细胞因子（如白介素-I和肿瘤坏死因子-α）的抑制，已知它们可刺激II型NO合酶（iNOS）的表达。我们在这里报告说，泛素/ 26S蛋白酶体途径触发了平滑肌细胞中PKG-I蛋白水平的抑制。用抗磷酸二酯酶的环状GMP类似物（例如8-溴-cGMP）孵育血管平滑肌细胞以时间和浓度依赖性方式降低PKG-1蛋白水平。为了研究该过程，我们测试了8-Br-cGMP对Cos7细胞中PKG-1蛋白水平的影响，该Cos7细胞不表达内源性I型PKG mRNA。 8-Br-cGMP诱导了PKG-1α的泛素化和下调，但不引起PKG-1β的泛素化和下调。用26S蛋白酶体抑制剂MG-132处理细胞会增加PKG的泛素化。使用可透过细胞的特异性PKG-1抑制剂DT-2阻断PKG-1催化活性，可抑制cGMP诱导的PKG-1泛素化和下调，这表明抑制PKG-1水平需要PKG催化活性和自磷酸化作用。将已知的PKG-1α自磷酸化位点突变为丙氨酸，揭示了cGMP依赖性泛素化和PKG-1水平抑制中丝氨酸64自身磷酸化的特定作用。结果表明，如在炎症条件下所见，cGMP的慢性升高会触发平滑肌中PKG-1α的泛素化和降解。

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