CYLD-mediated lysine63 deubiquitination regulates synaptic transmission and autophagy to mitigate age-related sequelae.

Lysine63 polyubiquitination is a prevalent post-translational modification in the central nervous system. Deficiency of CYLD, a lysine63-specific deubiquitinase, is linked to synaptic dysfunction and neurodegenerative disorders. However, our understanding of how CYLD contributes to the manifestation of neuronal deficits, particularly in the context of ageing, remains limited. Here, we report that CYLD-1 is essential for physiological lifespan in the nematode Caenorhabditis elegans. Neuronal CYLD-1 supports cholinergic neurotransmission and GABAergic synapse integrity, ensuring intact locomotory capacity, as well as learning and memory competence. Specifically, the deubiquitinase activity of CYLD-1 is necessary for upholding cholinergic neurotransmission and lifespan. We further show that CYLD-1 regulates autolysosomal and lysosomal network organisation in neurons and peripheral tissues in vivo. Our work unveils a crucial role of CYLD-1 in optimizing neural activity and behavioural outcomes, to improve organismal fitness and survival.