AbstractCLN5 is a soluble endolysosomal protein that regulates the itinerary of the lysosomal sorting receptor sortilin. Mutations in this protein cause neuronal ceroid lipofuscinosis, a rare neurodegenerative disorder, and have also been associated with Alzheimer’s disease, suggesting functional defects in a common pathway. We previously found that depletion of CLN5 leads to dysfunctional retromer, resulting in the degradation of the lysosomal sorting receptor, sortilin. However, how a soluble lysosomal protein can modulate the function of a cytosolic protein is not known. In this work, we show that deletion of CLN5 not only results in retromer dysfunction, but also in impaired endolysosome fusion events. This results in delayed degradation of endocytic proteins and in defective autophagy. CLN5 modulates these various pathways by regulating downstream interactions between CLN3, an integral membrane protein, Rab7A and a subset of Rab7A effectors. Mutations in CLN3 are also a cause of neuronal ceroid lipofuscinosis. Our data supports a model where CLN3 and CLN5 function as an endolysosome complex regulating several endosomal functions.Summary StatementWe have previously demonstrated that CLN3 is required for efficient endosome-to-trans Golgi Network (TGN) trafficking of sortilin by regulating retromer function. In this work, we show that CLN5, which interacts with CLN3, regulates retromer function by modulating key interactions between CLN3, Rab7A, retromer, and sortilin. Therefore, CLN3 and CLN5 serve as endosomal switch regulating the itinerary of the lysosomal sorting receptors.
CLN5 and CLN3 function as a complex to regulate endolysosome function
