Jer1-Ga2-LpR1 axis mediates upstream input of alpha-mannosidosis.

Alpha-mannosidosis (AMD) is a well-known lysosomal storage disorder caused by the loss of α-mannosidase activity due to the mutation of the MAN2B1 gene. Defective α-mannosidase cannot completely degrade the sugar chains of upstream input glycoproteins, leading to the accumulation of oligosaccharides with α-mannosidic linkages in lysosomes, finally causing AMD. However, till now, the upstream input mediating AMD remains elusive, which hinders the development of alternative therapeutic treatments. To address this question, we establish the first Drosophila model of AMD and, through genetic screen, identify three novel upstream factors named Jer1, Ga2, and LpR1. We demonstrate that knocking down either of them can rescue the lethal phenotype of AMD flies and they mediate upstream input of AMD through a Jer1-Ga2-LpR1 axis. Mechanistically, Jer1 recruits the E3 ligase Ga2, which mediates the ubiquitination of the glycoprotein LpR1 for subsequent lysosomal degradation. Therefore, knockdown of Jer1 or Ga2 downregulates LpR1 ubiquitination and prevents it from degradation in lysosomes, reducing the burden on lysosomes and alleviating the symptoms of AMD. Importantly, our study further demonstrates that IPP, UBE3C, and VLDLR, the mammalian counterparts of Jer1, Ga2, and LpR1, respectively, are functionally conserved during evolution, suggesting that they can be used as potential therapeutic targets for the treatment of AMD.