Universität zu Köln

Pechincha, Catarina ORCID: 0000-0002-4650-4250, Groessl, Sven ORCID: 0000-0002-1339-7647, Kalis, Robert ORCID: 0000-0001-7553-4806, de Almeida, Melanie ORCID: 0000-0003-4871-2069, Zanotti, Andrea, Wittmann, Marten ORCID: 0000-0001-7327-9127, Schneider, Martin, de Campos, Rafael P., Rieser, Sarah ORCID: 0000-0001-5374-1871, Brandstetter, Marlene ORCID: 0000-0002-8134-4985, Schleiffer, Alexander, Mueller-Decker, Karin, Helm, Dominic, Jabs, Sabrina ORCID: 0000-0001-8065-8002, Haselbach, David, Lemberg, Marius K., Zuber, Johannes ORCID: 0000-0001-8810-6835 and Palm, Wilhelm (2022). Lysosomal enzyme trafficking factor LYSET enables nutritional usage of extracellular proteins. Science, 378 (6615). S. 39 - 49. WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE. ISSN 1095-9203

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Pechincha, Catarina UNSPECIFIED orcid.org/0000-0002-4650-4250 UNSPECIFIED Groessl, Sven UNSPECIFIED orcid.org/0000-0002-1339-7647 UNSPECIFIED Kalis, Robert UNSPECIFIED orcid.org/0000-0001-7553-4806 UNSPECIFIED de Almeida, Melanie UNSPECIFIED orcid.org/0000-0003-4871-2069 UNSPECIFIED Zanotti, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Wittmann, Marten UNSPECIFIED orcid.org/0000-0001-7327-9127 UNSPECIFIED Schneider, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED de Campos, Rafael P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rieser, Sarah UNSPECIFIED orcid.org/0000-0001-5374-1871 UNSPECIFIED Brandstetter, Marlene UNSPECIFIED orcid.org/0000-0002-8134-4985 UNSPECIFIED Schleiffer, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller-Decker, Karin UNSPECIFIED UNSPECIFIED UNSPECIFIED Helm, Dominic UNSPECIFIED UNSPECIFIED UNSPECIFIED Jabs, Sabrina UNSPECIFIED orcid.org/0000-0001-8065-8002 UNSPECIFIED Haselbach, David UNSPECIFIED UNSPECIFIED UNSPECIFIED Lemberg, Marius K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zuber, Johannes UNSPECIFIED orcid.org/0000-0001-8810-6835 UNSPECIFIED Palm, Wilhelm UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-692412
DOI:	10.1126/science.abn5637
Journal or Publication Title:	Science
Volume:	378
Number:	6615
Page Range:	S. 39 - 49
Date:	2022
Publisher:	AMER ASSOC ADVANCEMENT SCIENCE
Place of Publication:	WASHINGTON
ISSN:	1095-9203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MUCOLIPIDOSIS-II; ACID; PHOSPHOTRANSFERASE; METABOLISM; SUBUNIT Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/69241