GOLPH3 and GOLPH3L maintain Golgi localization of LYSET and a functional mannose 6-phosphate transport pathway
Glycosylation, which plays an important role in modifying lipids and sorting of proteins, is regulated by asymmetric intra-Golgi distribution and SPPL3-mediated cleavage of Golgi enzymes. We found that cells lacking LYSET/TMEM251, a retention factor for Golgi N-acetylglucosamine-1-phosphotransferase (GNPT), display SPPL3-dependent hypersecretion of the Golgi membrane protein B4GALT5. We demonstrate that in wild-type cells B4GALT5 is tagged with mannose 6-phosphate (M6P), a sorting tag typical of soluble lysosomal hydrolases. Hence, M6P-tagging of B4GALT5 may represent a novel degradative lysosomal pathway. We also observed B4GALT5 hypersecretion and prominent destabilization of LYSET-GNPT complexes, impaired M6P-tagging, and disturbed maturation and trafficking of lysosomal enzymes in multiple human cell lines lacking the COPI adaptors GOLPH3 and GOLPH3L. Mechanistically, we identified LYSET as a novel, atypical client of GOLPH3/GOLPH3L. Thus, by ensuring the cis-Golgi localization of the LYSET-GNPT complex and maintaining its Golgi polarity, GOLPH3/GOLPH3L is essential for the integrity of the M6P-tagging machinery and homeostasis of lysosomes.
Authors
- Thomas Braulke (ORCID: https://orcid.org/0000-0002-2336-8532)
- Lynne M. Wagner
- Michaela Schweizer (ORCID: https://orcid.org/0000-0001-5062-328X)
- Yoshiki Narimatsu (ORCID: https://orcid.org/0000-0003-1428-5695)
- Daniel Meisinger
- Matthias Voß (ORCID: https://orcid.org/0000-0002-4217-3175)
- Lukas Blume (ORCID: https://orcid.org/0000-0003-1889-0470)
- Jan E. Carette (ORCID: https://orcid.org/0000-0002-5187-8070)
- Henrik Clausen (ORCID: https://orcid.org/0000-0002-0915-5055)
- Zilei Chen (ORCID: https://orcid.org/0000-0003-2300-9211)
- Wenjie Qiao (ORCID: https://orcid.org/0000-0002-0255-6155)
- Laura Hobohm (ORCID: https://orcid.org/0000-0001-6125-7940)
- Johannes Wienberg
- Dominic Winter (ORCID: https://orcid.org/0000-0001-6788-6641)
- Brooke L. Brauer (ORCID: https://orcid.org/0009-0007-6855-5175)
- Sabrina Jabs (ORCID: https://orcid.org/0000-0001-8065-8002)
- Jiaran Li (ORCID: https://orcid.org/0000-0002-9951-4671)
- Felix Beirow
- Emanuela Capriotti
Institutions
- University of Copenhagen (DK)
- University of Bonn (DE)
- Universität Hamburg (DE)
- Hochschule für Angewandte Wissenschaften Kiel (DE)
- Christian-Albrechts-Universität zu Kiel (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- University Hospital Schleswig-Holstein (DE)
- University of Lübeck (DE)
- Stanford University (US)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2024-11-25
- DOI
- https://doi.org/10.1038/s44318-024-00305-z
- Citations
- 19
- Primary Topic
- Cellular transport and secretion
- Type
- article
- Field-Weighted Citation Impact
- 6.19
Funders
- Deutsche Forschungsgemeinschaft
- Christian-Albrechts-Universität zu Kiel
- Fritz Thyssen Stiftung
- China Scholarship Council
- Novo Nordisk Fonden