A UPF3-mediated regulatory switch that maintains RNA surveillance
A UPF3-mediated regulatory switch that maintains RNA surveillance
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DOI：
10.1038/nsmb.1612
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发表时间：
2009-07-01
影响因子：
16.8
通讯作者：
Wilkinson, Miles F.
中科院分区：
文献类型：
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作者：
Chan, Wai-Kin;Bhalla, Angela D.;Wilkinson, Miles F.
无义介导的衰变（NMD）是一种下调异常mrna和正常mrna子集的RNA衰变途径。人们对NMD的调控知之甚少。在这里，我们确定了一种作用于两个相关UPF（上移码）因子的调节机制，UPF3A和UPF3B对NMD至关重要。这种调节机制在UPF3B的存在下降低了UPF3A的水平，在UPF3B突变个体中得到缓解，导致UPF3A的稳态水平显著升高。UPF3A通过调节几种NMD靶转录物来弥补UPF3B的缺失，但它也会损害NMD，因为它与更强的NMD激活剂UPF3B竞争，以结合必要的NMD因子UPF2。UPF3A蛋白的这种有害作用是通过使用保守的UPF3A依赖机制使其不稳定来阻止的。总之，我们的研究结果表明，UPF3A水平受到转录后开关的严格调节，以在含有不同水平UPF3B的细胞中维持适当的NMD底物水平。
Nonsense-mediated decay (NMD) is an RNA decay pathway that downregulates aberrant mRNAs and a subset of normal mRNAs. The regulation of NMD is poorly understood. Here we identify a regulatory mechanism acting on two related UPF (up-frameshift) factors crucial for NMD: UPF3A and UPF3B. This regulatory mechanism, which reduces the level of UPF3A in response to the presence of UPF3B, is relieved in individuals harboring UPF3B mutations, leading to strongly increased steady-state levels of UPF3A. UPF3A compensates for the loss of UPF3B by regulating several NMD target transcripts, but it can also impair NMD, as it competes with the stronger NMD activator UPF3B for binding to the essential NMD factor UPF2. This deleterious effect of UPF3A protein is prevented by its destabilization using a conserved UPF3B-dependent mechanism. Together, our results suggest that UPF3A levels are tightly regulated by a post-transcriptional switch to maintain appropriate levels of NMD substrates in cells containing different levels of UPF3B.