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GRASP55 maintains lysosome function by controlling sorting of lysosomal enzymes at the Golgi.

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Τίτλος: GRASP55 maintains lysosome function by controlling sorting of lysosomal enzymes at the Golgi.
Συγγραφείς: Nüchel J; Max Planck Institute for Biology of Ageing (MPI-AGE), Cologne, Germany. nuechel.julian@uni-koeln.de.; University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Biochemistry, Cologne, Germany. nuechel.julian@uni-koeln.de.; University of Cologne, Center for Molecular Medicine Cologne (CMMC), Cologne, Germany. nuechel.julian@uni-koeln.de., Omidi M; Department of Osteology and Biomechanics (IOBM), University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Fernandes SA; Max Planck Institute for Biology of Ageing (MPI-AGE), Cologne, Germany., Tauber M; University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Biochemistry, Cologne, Germany., Pohl S; Department of Osteology and Biomechanics (IOBM), University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Plomann M; University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Biochemistry, Cologne, Germany., Demetriades C; Max Planck Institute for Biology of Ageing (MPI-AGE), Cologne, Germany. Demetriades@age.mpg.de.; University of Cologne, Cologne Excellence Cluster for Aging and Aging-Associated Diseases (CECAD), Cologne, Germany. Demetriades@age.mpg.de.; European Research Institute for the Biology of Ageing (ERIBA), University of Groningen (RUG), University Medical Center Groningen (UMCG), Groningen, The Netherlands. Demetriades@age.mpg.de.
Πηγή: EMBO reports [EMBO Rep] 2026 Jun; Vol. 27 (11), pp. 2947-2972. Date of Electronic Publication: 2026 Apr 16.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 100963049 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1469-3178 (Electronic) Linking ISSN: 1469221X NLM ISO Abbreviation: EMBO Rep Subsets: MEDLINE
Imprint Name(s): Publication: 2024- : [London] : Nature Publishing Group
Original Publication: Oxford, UK : Published for EMBO by Oxford University Press, 2000-
Ιατρικοί όροι (MeSH): Lysosomes*/metabolism , Lysosomes*/enzymology , Golgi Apparatus*/metabolism , Membrane Proteins*/metabolism , Membrane Proteins*/genetics, Golgi Matrix Proteins/metabolism ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; Multiprotein Complexes/metabolism ; TOR Serine-Threonine Kinases/metabolism ; Humans ; Mechanistic Target of Rapamycin Complex 1 ; Protein Transport ; Signal Transduction ; Phosphorylation ; Animals ; Protein Binding ; HeLa Cells
Περίληψη: Lysosomes are multifunctional organelles that play important roles in cellular recycling, signaling, and homeostasis, relying on precise trafficking and activation of lysosomal enzymes. While the Golgi apparatus plays a central role in lysosomal enzyme sorting, the mechanisms linking Golgi function to lysosomal activity remain incompletely understood. Here, we identify the Golgi-resident protein GRASP55, but not its paralog GRASP65, as necessary for lysosome function. Loss of GRASP55 expression leads to missorting and secretion of lysosomal enzymes, lysosomal dysfunction and bloating. GRASP55 deficiency also disrupts lysosomal mTORC1 signaling, reducing the phosphorylation of its lysosomal substrates TFEB/TFE3, while sparing its non-lysosomal targets. Mechanistically, GRASP55 binds and maintains the COPI adaptor GOLPH3 protein at the Golgi, thereby controlling the Golgi localization and stability of LYSET and GNPTAB that are required for mannose 6-phosphate (M6P) tagging of lysosomal enzymes. These findings reveal an essential role for GRASP55 in Golgi-lysosome communication and lysosomal enzyme trafficking and underscore the importance of Golgi-mediated protein sorting in lysosome function and lysosomal mTORC1 signaling.
(© 2026. The Author(s).)
Competing Interests: Disclosure and competing interests statement. The authors declare no competing interests.
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Grant Information: 757729 EC | Horizon 2020 Framework Programme (H2020); DE 3170/1-1 Deutsche Forschungsgemeinschaft (DFG); PO 1539/1-2 Deutsche Forschungsgemeinschaft (DFG); NU 467/1-1 Deutsche Forschungsgemeinschaft (DFG); N/A Max-Planck-Gesellschaft (MPG); Project C10 UoC | Center for Molecular Medicine Cologne, University of Cologne (CMMC, UoC); Project CAP31 UoC | Center for Molecular Medicine Cologne, University of Cologne (CMMC, UoC)
Substance Nomenclature: EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
0 (Membrane Proteins)
0 (Golgi Matrix Proteins)
0 (Basic Helix-Loop-Helix Leucine Zipper Transcription Factors)
0 (Multiprotein Complexes)
0 (GOLPH3 protein, human)
0 (TFEB protein, human)
0 (GORASP2 protein, human)
EC 2.7.11.1 (TOR Serine-Threonine Kinases)
0 (GORASP1 protein, human)
Entry Date(s): Date Created: 20260416 Date Completed: 20260613 Latest Revision: 20260813
Update Code: 20260813
PubMed Central ID: PMC13261057
DOI: 10.1038/s44319-026-00773-w
PMID: 41991615
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1469-3178
DOI:10.1038/s44319-026-00773-w