Lysosomal enzyme trafficking factor LYSET enables nutritional usage of extracellular proteins

  • Science. 2022 Oct 7;378(6615):eabn5637. doi: 10.1126/science.abn5637.
Catarina Pechincha  1  2 ,  Sven Groessl  #  1  2 ,  Robert Kalis  #  3  4 ,  Melanie de Almeida  3  4 ,  Andrea Zanotti  5 ,  Marten Wittmann  1 ,  Martin Schneider  6 ,  Rafael P de Campos  1  2 ,  Sarah Rieser  3  4 ,  Marlene Brandstetter  7 ,  Alexander Schleiffer  3 ,  Karin Müller-Decker  8 ,  Dominic Helm  6 ,  Sabrina Jabs  9 ,  David Haselbach  3  10 ,  Marius K Lemberg  5  11 ,  Johannes Zuber  3  12 ,  Wilhelm Palm  1
Affiliations
  • 1. Cell Signaling and Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 2. Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany.
  • 3. Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Vienna, Austria.
  • 4. VBC PhD Program, Doctoral School of the University at Vienna and Medical University of Vienna, VBC, Vienna, Austria.
  • 5. Center for Molecular Biology of Heidelberg University (ZMBH), Heidelberg, Germany.
  • 6. MS-based Protein Analysis Unit, Genomics and Proteomics Core Facility, DKFZ, Heidelberg, Germany.
  • 7. Electron Microscopy Facility, VBC Core Facilities GmbH, Vienna, Austria.
  • 8. Core Facility Tumor Models, DKFZ, Heidelberg, Germany.
  • 9. Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany.
  • 10. Institute of Physical Chemistry, University of Freiburg, Freiburg, Germany.
  • 11. Center for Biochemistry and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Faculty of Medicine, University of Cologne, Cologne, Germany.
  • 12. Medical University of Vienna, VBC, Vienna, Austria.
  • # Contributed equally.
PMID: 36074822 DOI: 10.1126/science.abn5637
Abstract

Mammalian cells can generate Amino acids through macropinocytosis and lysosomal breakdown of extracellular proteins, which is exploited by Cancer cells to grow in nutrient-poor tumors. Through genetic screens in defined nutrient conditions, we characterized LYSET, a transmembrane protein (TMEM251) selectively required when cells consume extracellular proteins. LYSET was found to associate in the Golgi with GlcNAc-1-phosphotransferase, which targets catabolic Enzymes to lysosomes through mannose-6-phosphate modification. Without LYSET, GlcNAc-1-phosphotransferase was unstable because of a hydrophilic transmembrane domain. Consequently, LYSET-deficient cells were depleted of lysosomal Enzymes and impaired in turnover of macropinocytic and autophagic cargoes. Thus, LYSET represents a core component of the lysosomal enzyme trafficking pathway, underlies the pathomechanism for hereditary lysosomal storage disorders, and may represent a target to suppress metabolic adaptations in Cancer.