@article{3003734,
    title = "BsdABsd2-dependent vacuolar turnover of a misfolded version of the UapA transporter along the secretory pathway: Prominent role of selective autophagy",
    author = "Evangelinos, M. and Martzoukou, O. and Chorozian, K. and Amillis, S. and Diallinas, G.",
    journal = "Molecular Microbiology",
    year = "2016",
    volume = "100",
    number = "5",
    pages = "893-911",
    publisher = "Wiley-Blackwell Publishing Ltd",
    issn = "0950-382X, 1365-2958",
    doi = "10.1111/mmi.13358",
    keywords = "bacterial protein;  BsdABsd2 protein;  HulARsp5 protein;  membrane protein;  UapA protein;  ubiquitin protein ligase;  unclassified drug;  carrier protein;  fungal protein;  UAPA protein, Aspergillus nidulans, Article;  Aspergillus nidulans;  autophagy;  bioaccumulation;  controlled study;  endoplasmic reticulum;  in vivo study;  molecular dynamics;  nonhuman;  priority journal;  protein determination;  protein function;  protein localization;  protein metabolism;  protein protein interaction;  protein unfolding;  secretory pathway;  steady state;  autophagy;  cell vacuole;  chemistry;  genetics;  metabolism;  mutation;  physiology;  protein degradation;  protein folding;  protein transport, Aspergillus nidulans;  Autophagy;  Endoplasmic Reticulum;  Fungal Proteins;  Membrane Transport Proteins;  Mutation;  Protein Folding;  Protein Transport;  Proteolysis;  Secretory Pathway;  Vacuoles",
    abstract = "Transmembrane proteins translocate cotranslationally in the endoplasmic reticulum (ER) membrane and traffic as vesicular cargoes, via the Golgi, in their final membrane destination. Misfolding in the ER leads to protein degradation basically through the ERAD/proteasome system. Here, we use a mutant version of the purine transporter UapA (ΔR481) to show that specific misfolded versions of plasma membrane cargoes undergo vacuolar turnover prior to localization in the plasma membrane. We show that non-endocytic vacuolar turnover of ΔR481 is dependent on BsdABsd2, an ER transmembrane adaptor of HulARsp5 ubiquitin ligase. We obtain in vivo evidence that BsdABsd2 interacts with HulARsp5 and ΔR481, primarily in the ER. Importantly, accumulation of ΔR481 in the ER triggers delivery of the selective autophagy marker Atg8 in vacuoles along with ΔR481. Genetic block of autophagy (atg9Δ, rabOts) reduces, but does not abolish, sorting of ΔR481 in the vacuoles, suggesting that a fraction of the misfolded transporter might be redirected for vacuolar degradation via the Golgi. Our results support that multiple routes along the secretory pathway operate for the detoxification of Aspergillus nidulans cells from misfolded membrane proteins and that BsdA is a key factor for marking specific misfolded cargoes. A misfolded version of UapA transporter (ΔR481) partially escapes ERAD and is degraded in vacuoles via a non-endocytic pathway. ΔR481 vacuolar degradation is dependent on its interaction with the BsdA ER-adaptor of HulA ubiquitin ligase. Selective autophagy is shown to be the primary mechanism for ΔR481 vacuolar degradation, although degradation can also take place via Golgi traffic in autophagy deficient mutants. In conclusion, multiple overlapping turnover mechanisms seem to detoxify A. nidulans from misfolded transporters. © 2016 John Wiley & Sons Ltd."
}