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传导、细胞死亡调节和宿主-病原体相互作用中经典 NF-κB 通路的激活。在这里，我们通过促进蛋白质聚集体的自噬体清除来确定 NEMO 在蛋白质稳态调节中的独立于 NF-κB 的功能。 NEMO 缺陷细胞在蛋白毒性应激下积累错误折叠的蛋白质，并且容易受到蛋白质稳态挑战。此外，一名 NEMO 编码IKBKG基因突变导致 NEMO 与线性泛素链结合缺陷的患者出现了广泛的混合性脑蛋白病，包括 α-突触核蛋白、tau 和 TDP-43 病理学。 NEMO 放大 α-突触核蛋白聚集体的线性泛素化，并促进 p62 局部集中到病灶中。在体外，NEMO 降低了 p62 泛素依赖性相变所需的阈值浓度。总之，NEMO 通过在聚集体界面处提供有利于与 p62 共缩合的流动相来重塑聚集体表面，以实现有效的自噬体清除。