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Lysosomal enzyme trafficking factor LYSET enables nutritional usage of extracellular proteins

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) s...

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Main Authors: Pechincha, Catarina (Author) , Größl, Sven (Author) , Kalis, Robert (Author) , Almeida, Melanie de (Author) , Zanotti, Andrea (Author) , Wittmann, Marten (Author) , Schneider, Martin (Author) , Campos, Rafael P. de (Author) , Rieser, Sarah (Author) , Brandstetter, Marlene (Author) , Schleiffer, Alexander (Author) , Müller-Decker, Karin (Author) , Helm, Dominic (Author) , Jabs, Sabrina (Author) , Haselbach, David (Author) , Lemberg, Marius (Author) , Zuber, Johannes (Author) , Palm, Wilhelm (Author)
Format: Article (Journal)
Language:English
Published: 8 Sep 2022
In: Science
Year: 2022, Volume: 378, Issue: 6615, Pages: 1-10
ISSN:1095-9203
DOI:10.1126/science.abn5637
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1126/science.abn5637
Verlag, lizenzpflichtig, Volltext: https://www.science.org/doi/10.1126/science.abn5637
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Author Notes:Catarina Pechincha, Sven Groessl, Robert Kalis, Melanie de Almeida, Andrea Zanotti, Marten Wittmann, Martin Schneider, Rafael P. de Campos, Sarah Rieser, Marlene Brandstetter, Alexander Schleiffer, Karin Müller-Decker, Dominic Helm, Sabrina Jabs, David Haselbach, Marius K. Lemberg, Johannes Zuber, Wilhelm Palm
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Summary: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.
Item Description:Gesehen am 27.06.2023
Physical Description:Online Resource
ISSN:1095-9203
DOI:10.1126/science.abn5637

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