Ubiquilins Regulate Autophagic Flux through mTOR Signaling and Lysosomal Acidification

Abstract

Although the etiology of ALS remains poorly understood, impaired proteostasis is a common feature of different forms of ALS. Mutations in Ubiquilins, UBQLN2 and UBQLN4, cause familial ALS. The role of UBQLNs in proteasomal degradation is well established but their role in autophagy-lysosomal clearance is poorly defined. Here, we describe a crosstalk between ER stress, mTOR signaling, and autophagic flux in Drosophila and mammalian cells lacking Ubiquilins. We found that loss of Ubiquilins leads to ER stress, impairs mTORC1 activity, promotes autophagy, and causes the demise of neurons. We show that ubiquilin mutants display defective autophagic flux due to reduced lysosome acidification. Ubiquilins are required to maintain proper levels of V0a/V100 subunit of the v-ATPase and lysosomal pH. Feeding flies acidic nanoparticles alleviates defective autophagic flux in ubiquilin mutants. Hence, our studies reveal a conserved role for Ubiquilins as regulators of autophagy by controlling v-ATPase activity and mTOR signaling.