Lysosomal enzyme trafficking factor LYSET enables nutritional usage of extracellular proteins-Reference-Cited by-同舟云学术

Lysosomal enzyme trafficking factor LYSET enables nutritional usage of extracellular proteins

Published:2022-10-07 Issue:6615 Volume:378 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Pechincha Catarina¹²^ORCID,Groessl Sven¹²^ORCID,Kalis Robert³⁴^ORCID,de Almeida Melanie³⁴^ORCID,Zanotti Andrea⁵^ORCID,Wittmann Marten¹^ORCID,Schneider Martin⁶,de Campos Rafael P.¹²^ORCID,Rieser Sarah³⁴^ORCID,Brandstetter Marlene⁷^ORCID,Schleiffer Alexander³^ORCID,Müller-Decker Karin⁸,Helm Dominic⁶^ORCID,Jabs Sabrina⁹^ORCID,Haselbach David³¹⁰^ORCID,Lemberg Marius K.⁵¹¹^ORCID,Zuber Johannes³¹²^ORCID,Palm Wilhelm¹^ORCID

Affiliation:

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.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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