NEMO reshapes the α-Synuclein aggregate interface and acts as an autophagy adapter by co-condensation with p62

NEMO is a ubiquitin-binding protein which regulates canonical NF-kappa B pathway activation in innate immune signaling, cell death regulation and host-pathogen interactions. Here we identify an NF-kappa B-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 alpha-synuclein, tau and TDP-43 pathology. NEMO amplifies linear ubiquitylation at alpha-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. Selective autophagy helps to degrade aggregated proteins accumulating in neurodegenerative diseases. Here, the authors show that NEMO, a ubiquitin binding protein previously linked to innate immune signaling, is recruited to misfolded proteins and promotes their autophagic clearance by forming condensates with the autophagy receptor p62.