Targeted protein degradation (TPD) mediated by PROTACs (proteolysis targeting chimeras) or molecular glues is an emerging therapeutic strategy. Despite greater than 600 E3 ligases and their associated components, a limited number have been deployed in TPD. Those commonly used include cereblon (CRBN) and von Hippel-Lindau tumor suppressor (VHL), which are expressed widely and for which high affinity ligands are available. Limiting TPD to specific cells or tissues would be desirable in many settings. To this goal we have determined the potential of two erythroid cell-enriched E3 ligases, TRIM10 and TRIM58, to degrade a protein of interest, BCL11A, a validated therapeutic target for the β-hemoglobinopathies. We established a general strategy in which heterologous recognition domains replace the PRY-SPRY domain of TRIM10 and TRIM58. Recruitment of TRIM10 or TRIM58 to BCL11A by coiled-coil peptides, nanobodies, or the substrate recognition domain of CRBN led to its degradation. Our findings illustrate a strategy that may be widely useful in evaluating the TPD potential of other E3 ubiquitin ligases and provide a rationale for discovery of ligands for TRIM10 and TRIM58 for erythroid-selective depletion of proteins of interest.

中文翻译：

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重定向 E3 泛素连接酶，用于使用异源识别结构域进行靶向蛋白质降解。


由 PROTAC（蛋白水解靶向嵌合体）或分子胶介导的靶向蛋白质降解 （TPD） 是一种新兴的治疗策略。尽管有超过 600 种 E3 连接酶及其相关组分，但在 TPD 中部署的剂量有限。常用的包括 cereblon （CRBN） 和 von Hippel-Lindau 抑癌基因 （VHL），它们表达广泛，并且可以使用高亲和力配体。在许多情况下，将 TPD 限制在特定细胞或组织是可取的。为此，我们确定了两种富含红细胞的 E3 连接酶 TRIM10 和 TRIM58 降解目标蛋白 BCL11A 的潜力，BCL11A 是 β 血红蛋白病的经过验证的治疗靶标。我们建立了一个通用策略，其中异源识别结构域取代了 TRIM10 和 TRIM58 的 PRY-SPRY 结构域。卷曲螺旋肽、纳米抗体或 CRBN 的底物识别结构域将 TRIM10 或 TRIM58 募集到 BCL11A 导致其降解。我们的研究结果说明了一种策略，该策略可能在评估其他 E3 泛素连接酶的 TPD 潜力方面广泛有用，并为发现 TRIM10 和 TRIM58 的配体提供了基本原理，用于目标蛋白质的红细胞选择性耗竭。