Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Hills Road, Cambridge, CB2 0XZ, UK.
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QR, UK.
Sci Rep. 2018 Mar 15;8(1):4625. doi: 10.1038/s41598-018-23056-4.
The proneural transcription factor Ascl1 is a master regulator of neurogenesis, coordinating proliferation and differentiation in the central nervous system. While its expression is well characterised, post-translational regulation is much less well understood. Here we demonstrate that a population of chromatin-bound Ascl1 can be found associated with short chains of ubiquitin while cytoplasmic Ascl1 harbours much longer ubiquitin chains. Only cytoplasmic ubiquitylation targets Ascl1 for destruction, which occurs by conjugation of ubiquitin to lysines in the basic helix-loop-helix domain of Ascl1 and requires the E3 ligase Huwe1. In contrast, chromatin-bound Ascl1 associated with short ubiquitin-chains, which can occur on lysines within the N-terminal region or the bHLH domain and is not mediated by Huwe1, is not targeted for ubiquitin-mediated destruction. We therefore offer further insights into post-translational regulation of Ascl1, highlighting complex regulation of ubiquitylation and degradation in the cytoplasm and on chromatin.
神经前体细胞转录因子 Ascl1 是神经发生的主要调节因子，协调中枢神经系统中的增殖和分化。虽然其表达已经得到很好的描述，但翻译后调控的理解要少得多。在这里，我们证明了可以发现一群与短链泛素结合的染色质结合的 Ascl1，而细胞质中的 Ascl1 则具有更长的泛素链。只有细胞质泛素化将 Ascl1 作为破坏的靶标，这是通过将泛素连接到 Ascl1 的碱性螺旋-环-螺旋结构域中的赖氨酸上发生的，需要 E3 连接酶 Huwe1。相比之下，与短泛素链结合的染色质结合的 Ascl1 不会被 Huwe1 介导的泛素化破坏，这些短泛素链可以发生在 N 端区域或 bHLH 结构域中的赖氨酸上。因此，我们提供了对 Ascl1 翻译后调控的进一步了解，突出了细胞质和染色质上泛素化和降解的复杂调控。
