Mesoscale regulation of microtubule-organising centres by the E3 ligase TRIM37

Centrosomes ensure accurate chromosome segregation during cell division. Although the regulation of centrosome number is well-established, less is known about the suppression of non-centrosomal Microtubule-Organising Centres (ncMTOCs). The E3 ligase TRIM37, implicated in Mulibrey nanism and 17q23-amplified cancers, has emerged as a key regulator of both centrosomes and ncMTOCs. Yet, the mechanism by which TRIM37 achieves enzymatic activation to target these mesoscale structures had thus far remained unknown. Here, we elucidate the activation process of TRIM37, unveiling a process that initiates with TRAF domain-directed substrate recognition, followed by B-box domain-mediated oligomerisation, and culminates in RING domain dimerisation. Using optogenetics, we demonstrate that the E3 activity of TRIM37 is directly coupled to the assembly state of its substrates, being activated only when centrosomal proteins cluster into higher-order assemblies resembling MTOCs. This regulatory framework provides a mechanistic basis for understanding TRIM37-driven pathologies and echoes the restriction of the HIV capsid by TRIM5, thus unveiling a conserved activation blueprint among TRIM proteins to control turnover of complexes assembled at the mesoscale level.

中心体（Centrosomes）在细胞分裂过程中保障染色体精准分离。尽管学界对中心体数量的调控机制已有充分阐明，但针对非中心体微管组织中心（non-centrosomal Microtubule-Organising Centres, ncMTOCs）的抑制机制仍有待深入解析。与穆利布瑞侏儒症及17q23扩增型癌症相关的E3泛素连接酶（E3 ligase）TRIM37，现已被证实是调控中心体与ncMTOCs的关键因子。然而，TRIM37如何通过酶活激活以靶向此类介观尺度结构的分子机制，此前始终未被揭示。本研究阐明了TRIM37的完整激活流程：其起始于TRAF结构域（TRAF domain）介导的底物识别，随后经由B-box结构域（B-box domain）介导的寡聚化，最终以RING结构域（RING domain）二聚化完成激活。我们通过光遗传学（optogenetics）实验证实，TRIM37的E3连接酶活性直接与其底物的组装状态耦合：仅当中心体蛋白聚集形成类似微管组织中心的高阶组装体时，TRIM37才会被激活。该调控框架为理解TRIM37驱动的病理机制提供了机制性理论基础，其与TRIM5限制HIV衣壳（HIV capsid）的调控策略高度相似，由此揭示了TRIM家族蛋白中保守的激活范式，用于调控介观尺度组装复合物的周转。