Wagner Kristina, Keiten-Schmitz Jan, Adhikari Bikash, Patra Upayan, Husnjak Koraljka, McNicoll François, Dormann Dorothee, Müller-McNicoll Michaela, Tascher Georg, Wolf Elmar, Müller Stefan
Institute of Biochemistry II, Goethe University Frankfurt, Faculty of Medicine, Frankfurt am Main, Germany.
Biochemisches Institut, Christian-Albrechts-Universität, Kiel, Germany.
Nat Chem Biol. 2025 Apr 17. doi: 10.1038/s41589-025-01886-4.
The established role of cytosolic and nuclear inclusions of TDP-43 in the pathogenesis of neurodegenerative disorders has multiplied efforts to understand mechanisms that control TDP-43 aggregation and has spurred searches for approaches limiting this process. Formation and clearance of TDP-43 aggregates are controlled by an intricate interplay of cellular proteostasis systems that involve post-translational modifications and frequently rely on spatial control. We demonstrate that attachment of the ubiquitin-like SUMO2 modifier compartmentalizes TDP-43 in promyelocytic leukemia protein (PML) nuclear bodies and limits the aggregation of TDP-43 in response to proteotoxic stress. Exploiting this pathway through proximity-inducing recruitment of TDP-43 to PML triggers a SUMOylation-ubiquitylation cascade protecting TDP-43 from stress-induced insolubility. The protective function of PML is mediated by ubiquitylation in conjunction with the p97 disaggregase. Altogether, we demonstrate that SUMO-ubiquitin networks protect cells from insoluble TDP-43 inclusions and propose the functionalization of PML as a potential future therapeutic avenue countering aggregation.
TDP - 43在细胞溶质和细胞核中的包涵体在神经退行性疾病发病机制中已明确的作用，促使人们加倍努力去了解控制TDP - 43聚集的机制，并激发了对限制这一过程方法的探索。TDP - 43聚集体的形成和清除受细胞蛋白质稳态系统复杂相互作用的控制，该系统涉及翻译后修饰且常常依赖空间控制。我们证明，类泛素化修饰SUMO2附着使TDP - 43定位于早幼粒细胞白血病蛋白（PML）核体中，并在蛋白毒性应激反应中限制TDP - 43的聚集。通过将TDP - 43临近诱导募集到PML来利用这一途径，会触发SUMO化 - 泛素化级联反应，保护TDP - 43免受应激诱导的不溶性影响。PML的保护功能由泛素化结合p97解聚酶介导。总之，我们证明SUMO - 泛素网络保护细胞免受不溶性TDP - 43包涵体的影响，并提出将PML功能化作为对抗聚集的潜在未来治疗途径。
