title: Ubpy controls the stability of the ESCRT-0 subunit Hrs in development.
abstract: Ubiquitylated developmental membrane signaling proteins are often internalized for endocytic trafficking, through which endosomal sorting complexes required for transport (ESCRT) act sequentially to deliver internalized cargos to lysosomes. The ESCRT function in endocytic sorting is well established; however, it is not fully understood how the sorting machinery itself is regulated. Here, we show that Ubiquitin isopeptidase Y (Ubpy) plays a conserved role in vivo in the homeostasis of an essential ESCRT-0 complex component Hrs. We find that, in the absence of Drosophila Ubpy, multiple membrane proteins that are essential components of important signaling pathways accumulate in enlarged, aberrant endosomes. We further demonstrate that this phenotype results from endocytic pathway defects. We provide evidence that Ubpy interacts with and deubiquitylates Hrs. In Ubpy-null cells, Hrs becomes ubiquitylated and degraded in lysosomes, thus disrupting the integrity of ESCRT sorting machinery. Lastly, we find that signaling proteins are enriched in enlarged endosomes when Hrs activity is abolished. Together, our data support a model in which Ubpy plays a dual role in both cargo deubiquitylation and the ESCRT-0 stability during development.
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Peking-Tsinghua Center for Life Sciences, College of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Junzheng
authors.initials: J
authors.lastname: Zhang
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.forename: Cong
authors.initials: C
authors.lastname: Lei
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.forename: Alan Jian
authors.initials: AJ
authors.lastname: Zhu
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002478:Cells, Cultured; D029721:Drosophila Proteins / Q000502:physiology*; D004331:Drosophila melanogaster / Q000196:embryology* / Q000235:genetics; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D010750:Phosphoproteins / Q000378:metabolism*; D055550:Protein Stability; D021122:Protein Subunits / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000502:physiology*; D054875:Ubiquitination / Q000235:genetics; D014921:Wings, Animal / Q000196:embryology / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D010750:Phosphoproteins; D021122:Protein Subunits; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; D043222:Ubiquitin Thiolesterase
keywords: Developmental signaling; Drosophila; ESCRT-0; Endocytic machinery; Hrs; Ubpy