2. Academic Validation
  3. Lysosomal enzyme trafficking factor LYSET enables nutritional usage of extracellular proteins

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

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.

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