Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea.
J Microbiol Biotechnol. 2013 Dec;23(12):1785-90. doi: 10.4014/jmb.1309.09027.
The synthetic machinery of ATF4 (activating transcription factor 4) is activated in response to various stress conditions involved in nutrient restriction, endoplasmic reticulum homeostasis, and oxidation. Stress-induced inhibition of proteasome activity triggers the unfolded protein response and endoplasmic reticulum stress, where ATF4 is crucial for consequent biological events. In the current study, we showed that the NAD(+)-dependent deacetylase, SIRT1, suppresses ATF4 synthesis during proteasome inhibition. SIRT1 depletion via transfection of specific siRNA into HeLa cells resulted in a significant increase in ATF4 protein, which was observed specifically in the presence of the proteasome inhibitor MG132. Consistent with SIRT1 depletion data, transient transfection of cells with SIRT1-overexpressing plasmid induced a decrease in the ATF4 protein level in the presence of MG132. Interestingly, however, ATF4 mRNA was not affected by SIRT1, even in the presence of MG132, indicating that SIRT1-induced suppression of ATF4 synthesis occurs under post-transcriptional control. Accordingly, we propose that SIRT1 serves as a negative regulator of ATF4 protein synthesis at the post-transcriptional level, which is observed during stress conditions, such as proteasome inhibition.
ATF4（激活转录因子 4）的合成机制被激活，以响应涉及营养限制、内质网稳态和氧化的各种应激条件。应激诱导的蛋白酶体活性抑制会引发未折叠蛋白反应和内质网应激，而 ATF4 对于随后的生物学事件至关重要。在本研究中，我们表明 NAD（+）依赖性去乙酰化酶 SIRT1 在蛋白酶体抑制时抑制 ATF4 的合成。通过将特定的 siRNA 转染到 HeLa 细胞中，SIRT1 的耗竭导致 ATF4 蛋白的显著增加，这种增加仅在存在蛋白酶体抑制剂 MG132 时观察到。与 SIRT1 耗竭数据一致的是，在存在 MG132 的情况下，用 SIRT1 过表达质粒瞬时转染细胞会导致 ATF4 蛋白水平降低。然而，有趣的是，ATF4 mRNA 不受 SIRT1 影响，即使存在 MG132，这表明 SIRT1 诱导的 ATF4 合成抑制是在转录后水平发生的。因此，我们提出 SIRT1 作为 ATF4 蛋白合成的负调节剂，在应激条件下（如蛋白酶体抑制）观察到这种调节。
