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Mechanisms Directing the Nuclear Localization of the CtBP Family Proteins

机译：指导CtBP家族蛋白核定位的机制。

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The C-terminal binding protein (CtBP) family includes four proteins (CtBP1 [CtBP1-L], CtBP3/BARS [CtBP1-S], CtBP2, and RIBEYE) which are implicated both in transcriptional repression and in intracellular trafficking. However, the precise mechanisms by which different CtBP proteins are targeted to different subcellular regions remains unknown. Here, we report that the nuclear import of the various CtBP proteins and splice isoforms is differentially regulated. We show that CtBP2 contains a unique nuclear localization signal (NLS) located within its N-terminal region, which contributes to its nuclear accumulation. Using heterokaryon assays, we show that CtBP2 is capable of shuttling between the nucleus and cytoplasm of the cell. Moreover, CtBP2 can heterodimerize with CtBP1-L and CtBP1-S and direct them to the nucleus. This effect strongly depends on the CtBP2 NLS. PXDLS motif-containing transcription factors, such as BKLF, that bind CtBP proteins can also direct them to the nucleus. We also report the identification of a splice isoform of CtBP2, CtBP2-S, that lacks the N-terminal NLS and localizes to the cytoplasm. Finally, we show that mutation of the CtBP NADH binding site impairs the ability of the proteins to dimerize and to associate with BKLF. This reduces the nuclear accumulation of CtBP1. Our results suggest a model in which the nuclear localization of CtBP proteins is influenced by the CtBP2 NLS, by binding to PXDLS motif partner proteins, and through the effect of NADH on CtBP dimerization.
机译：C末端结合蛋白（CtBP）家族包括四个蛋白（CtBP1 [CtBP1-L]，CtBP3 / BARS [CtBP1-S]，CtBP2和RIBEYE），它们与转录抑制和细胞内运输有关。但是，将不同的CtBP蛋白靶向不同的亚细胞区域的精确机制仍然未知。在这里，我们报告说，各种CtBP蛋白和剪接同工型的核输入受到差异调节。我们显示CtBP2包含位于其N端区域内的一个独特的核定位信号（NLS），这有助于其核积累。使用异核体分析，我们表明CtBP2能够在细胞核和细胞质之间穿梭。此外，CtBP2可以与CtBP1-L和CtBP1-S异源二聚体，并将其导向细胞核。这种影响在很大程度上取决于CtBP2 NLS。结合CtBP蛋白的含PXDLS基序的转录因子（例如BKLF）也可以将其引导至细胞核。我们还报告了鉴定的CtBP2，CtBP2-S的剪接同工型，缺少N端NLS并定位于细胞质。最后，我们表明CtBP NADH结合位点的突变会损害蛋白质二聚化和与BKLF缔合的能力。这减少了CtBP1的核积累。我们的结果提出了一个模型，其中CtBP蛋白的核定位受CtBP2 NLS，与PXDLS基序伴侣蛋白结合以及NADH对CtBP二聚作用的影响。

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