Department Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, 44801, Bochum, Germany.
Department Biochemistry of Neurodegenerative Diseases, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, 44801, Bochum, Germany.
Nat Commun. 2023 Dec 19;14(1):8368. doi: 10.1038/s41467-023-44033-0.
NEMO is a ubiquitin-binding protein which regulates canonical NF-κB pathway activation in innate immune signaling, cell death regulation and host-pathogen interactions. Here we identify an NF-κB-independent function of NEMO in proteostasis regulation by promoting autophagosomal clearance of protein aggregates. NEMO-deficient cells accumulate misfolded proteins upon proteotoxic stress and are vulnerable to proteostasis challenges. Moreover, a patient with a mutation in the NEMO-encoding IKBKG gene resulting in defective binding of NEMO to linear ubiquitin chains, developed a widespread mixed brain proteinopathy, including α-synuclein, tau and TDP-43 pathology. NEMO amplifies linear ubiquitylation at α-synuclein aggregates and promotes the local concentration of p62 into foci. In vitro, NEMO lowers the threshold concentrations required for ubiquitin-dependent phase transition of p62. In summary, NEMO reshapes the aggregate surface for efficient autophagosomal clearance by providing a mobile phase at the aggregate interphase favoring co-condensation with p62.
NEMO 是一种泛素结合蛋白，可调节先天免疫信号、细胞死亡调控和宿主-病原体相互作用中的经典 NF-κB 通路激活。在这里，我们发现 NEMO 在蛋白稳态调控方面具有非 NF-κB 依赖性的功能，可促进自噬体清除蛋白聚集体。在蛋白毒性应激下，NEMO 缺陷细胞会积累错误折叠的蛋白质，并且容易受到蛋白稳态挑战的影响。此外，一名携带编码 IKBKG 基因的 NEMO 突变的患者，导致 NEMO 与线性泛素链的结合缺陷，发展为广泛的混合脑蛋白病，包括α-突触核蛋白、tau 和 TDP-43 病理学。NEMO 放大了α-突触核蛋白聚集体上的线性泛素化，并促进 p62 局部聚集到焦点中。在体外，NEMO 降低了 p62 依赖于泛素的相转变所需的阈值浓度。总之，NEMO 通过在聚集体相间提供一个有利于与 p62 共凝聚的流动相，重塑了聚集体表面，从而有效地进行自噬体清除。
