Ligand-induced degrons for studying nuclear functions
Ligand-induced degrons for studying nuclear functions
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DOI：
10.1016/j.ceb.2021.12.006
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发表时间：
2022-01-19
影响因子：
7.5
通讯作者：
Kanemaki, Masato T.
中科院分区：
文献类型：
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作者：
Kanemaki, Masato T.
蛋白质表达的条件性控制有助于核功能的研究，核功能是高度动态的，与增殖细胞的细胞周期密切相关。然而，以翻译前过程为目标的条件性方法，如siRNA和条件敲除，需要相对较长的时间来耗尽目标蛋白质；因此，存在积累次级效应的危险，这将在观察之前掩盖主要缺陷。因此，配体诱导的降解技术引起了人们的注意，即在诱导配体的存在下，通过泛素-蛋白酶体途径促进降解融合蛋白与E3泛素连接酶之间的联系，从而导致降解融合蛋白的急性耗竭。这些化学基因技术是基于一种免疫调节药物、以蛋白质分解为靶标的嵌合体或植物激素。在这里，我回顾了目前的配体诱导的降解子，并介绍了使用Dtag或生长素诱导的降解子鉴定新的核功能的成功案例。我还综述了最新的基于BRD4溴结构域的配体诱导的降解。最后，我讨论了DTag和AID方法之间的异同。
Conditional control of protein expression facilitates studies of nuclear functions, which are highly dynamic and tightly linked to the cell cycle in proliferating cells. However, conditional methodologies that target a pre-translational process, such as siRNA and conditional knockout, require a relatively long time for target protein depletion; thus, there is a danger of accumulation of secondary effects that would obscure the primary defect before observation. Therefore, ligand-induced degron technologies draw attention to archive acute depletion of a degron-fused protein via the ubiquitin-proteasome pathway in the presence of an inducing ligand that promotes the association between a degron-fused protein and an E3 ubiquitin ligase. These chemical-genetic technologies are based on an immunomodulatory drug, proteolysis-targeting chimera or a phytohormone. Here, I review the current ligand-induced degrons and present successful cases in which new nuclear functions were identified using dTAG or an auxin-inducible degron. I also review latest ligand-induced degrons based on the BRD4 bromo-domain. Finally, I discuss the similarities and differences between dTAG and AID methodologies.