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Cited by 3Cellular transport and secretionLysosomal Storage Disorders ResearchCalcium signaling and nucleotide metabolism

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Molecular insights into the regulation of GNPTαβ by LYSET

Open access
Yang, Xi, Doray, Balraj, Henn, Danielle, Venkatarangan, Varsha, Jennings, Benjamin C., Dong, Zhongzheng, Liang, Jiaxuan, Zhang, Weichao, Zhang, Bokai, Yu, Linchen, Chen, Liang, Kornfeld, Stuart, Li, Ming·2026·Nature Communications
DOI 10.1038/s41467-026-70402-6PMC PMC13106649

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Abstract

In vertebrates, newly synthesized lysosomal enzymes traffic to lysosomes through the mannose-6-phosphate (M6P) pathway. The Golgi membrane protein LYSET was recently discovered to regulate lysosome biogenesis by controlling the level of GlcNAc-1-phosphotransferase (GNPT). However, its working mechanism remained unclear. In this study, we demonstrate that LYSET is a two-transmembrane protein essential for GNPT stability, cleavage by Site-1 Protease (S1P), and enzymatic activity. We reconcile conflicting models by showing that LYSET enhances GNPT cleavage and prevents its mislocalization to lysosomes for degradation. We further establish that LYSET achieves this by interacting with GOLPH3 and retromer complexes to anchor the LYSET-GNPT complex at the Golgi. Alanine mutagenesis identified an F 4 XXR 7 motif in LYSET’s N-tail for GOLPH3 binding. The retromer further promotes Golgi retention by binding to the C-terminal of LYSET and recycling it from endolysosomes. Together, our findings reveal LYSET’s multifaceted role in stabilizing GNPT, retaining it at the Golgi, and ensuring the fidelity of the M6P pathway, thereby providing insights into its molecular function.

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Metadata

Authors
Yang, X., Doray, B., Henn, D., Venkatarangan, V., Jennings, B. C., Dong, Z., Liang, J., Zhang, W., Zhang, B., Yu, L., Chen, L., Kornfeld, S., & Li, M.
Affiliations
  • University of Denver (US)
  • Washington University in St. Louis (US)
  • University of Michigan (US)
Corresponding author
Li, Ming
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2026-03-11
Volume
17
Issue
1
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-026-70402-6
PMC
PMC13106649
OpenAlex
W7134921154
Cited by
3
References
2
Citations by year
2026: 2
FWCI
6.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD109346)
  • U.S. Department of Health & Human Services | NIH | NCI | Division of Cancer Epidemiology and Genetics, National Cancer Institute (R01CA008759)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
Keywords
lysosomal enzyme trafficking, lysosomal biogenesis, GOLPH3, retromer complex, Golgi retention, protein stability

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