Proteasome inhibition up-regulates inflammatory gene transcription induced by an atypical pathway of NF-kappaB activation.
Proteasome inhibition up-regulates inflammatory gene transcription induced by an atypical pathway of NF-kappaB activation.
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DOI：
10.1016/j.bcp.2009.10.006
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发表时间：
2010-03-01
影响因子：
5.8
通讯作者：
Ponnappan, Usha
中科院分区：
文献类型：
--
作者：
Cullen, Sarah J.;Ponnappan, Subramaniam;Ponnappan, Usha
蛋白酶体抑制已成为抑制NF-κB活性的同义词。然而，过度活跃的NF-κB反应通常伴随以蛋白酶体缺陷为标志的生理状况，即年龄增长、老年病和硼替佐米耐药性。这些自相矛盾的NF-κB反应可能不受蛋白酶体缺陷的影响，因为它们源于由不依赖于蛋白酶体的上游机制诱导的非典型NF-κB信号传导。虽然这种非典型途径不需要蛋白酶体进行NF-κB核转位，但蛋白酶体在调节核NF-κB中的作用仍有待研究。我们现在证明，蛋白酶体严格控制由这种非典型NF-κB途径调节的炎症介质的转录。蛋白酶体的蛋白水解活性介导NF-κB B亚基p65/RelA从炎症基因中去除，从而终止非典型NF-κ B依赖性转录反应。我们首次证明了26 S蛋白酶体复合物的19 S和20 S组分都被募集到炎症基因启动子中;此外，19 S和20 S复合物似乎在NF-κ B依赖性转录的负调控中发挥不同的作用。通过证明蛋白酶体调节非典型NF-κ B依赖性转录反应的终止，这些研究清楚地表明蛋白酶体在非典型NF-κB信号传导中的新的调节作用。此外，这些结果表明蛋白酶体功能降低和炎症增加之间存在潜在的相互作用，并可以解释为什么炎症伴随着蛋白酶体功能受损的生理条件，例如在年龄增长期间或硼替佐米治疗后。鉴于蛋白酶体在炎症消退中的这种作用，蛋白酶体功能的恢复可能构成干预慢性炎性疾病的新机制。
Proteasome inhibition has become synonymous with inhibition of NF-κB activity. However, hyperactive NF-κB responses often accompany physiological conditions marked by proteasomal defects, i.e. advancing age, geriatric diseases, and bortezomib resistance. These paradoxical NF-κB responses are likely to be impervious to proteasomal defects because they stem from atypical NF-κB signaling induced by upstream mechanisms which are proteasome-independent. While this atypical pathway does not require proteasome for NF-κB nuclear translocation, a role for proteasome in regulating nuclear NF-κB remains unexplored. We now demonstrate that proteasome stringently controls transcription of inflammatory mediators regulated by this atypical NF-κB pathway. Proteolytic activity of the proteasome mediates the removal of the NF-κB subunit, p65/RelA, from inflammatory genes, thereby terminating atypical NF-κB-dependent transcriptional responses. For the first time, we demonstrate that both 19S and 20S components of the 26S proteasome complex are recruited to an inflammatory gene promoter; additionally, the 19S and 20S complexes appear to play distinct roles in the negative regulation of NF-κB-dependent transcription. By demonstrating that proteasome regulates the termination of atypical NF-κB-dependent transcriptional responses, these studies clearly indicate a novel, regulatory role for proteasome in atypical NF-κB signaling. Moreover, these results signal a potential interplay between lowered proteasomal function and increased inflammation and may explain why inflammation accompanies physiological conditions under which proteasomal function is compromised, such as during advancing age or following bortezomib treatment. Given this role for proteasome in inflammation resolution, restoration of proteasome function may constitute a novel mechanism for intervening in chronic inflammatory diseases.
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