Mettl5 coordinates protein production and degradation of PERIOD to regulate sleep in Drosophila

Sleep is crucial for animal physiology, primarily governed by the brain, and disruptions are prevalent in various brain disorders. Mettl5 , associated with intellectual disability (ID) often accompanied by sleep disturbances, remains poorly understood in its role causing these disorders. Previous research demonstrated that Mettl5 forms a complex with Trmt112, influencing rRNA methylation. In our study, we explored sleep phenotypes due to Drosophila Mettl5 mutations. Rescue experiments pinpointed Mettl5 ’s predominant role in neurons and glia marked by Mettl5 -Gal4 in sleep regulation. Notably, a Trmt112 mutation mirrored these sleep disturbances, implicating translational regulation via the Mettl5/Trmt112 complex. Subsequent RNA-seq and Ribo-seq analyses unveiled downstream events from Mettl5 ^1bp mutations, revealing altered expression levels of proteasome components and Clock genes. Rescue experiments confirmed that the net increased PERIOD protein is responsible for the sleep phenotype. This investigation sheds light on ribosome, clock genes, and proteasome interplay in sleep regulation, underscoring protein synthesis and degradation’s integrative role. These findings could potentially provide an example of in vivo study of the function of rRNA methylation, expand our understanding of the role of protein homeostasis in sleep and inspire explanations on the ID related sleep phenotypes.