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GCAF(TMEM251) regulates lysosome biogenesis by activating the mannose-6-phosphate pathway

Author

Listed:
  • Weichao Zhang

    (University of Michigan)

  • Xi Yang

    (University of Michigan)

  • Yingxiang Li

    (University of Michigan)

  • Linchen Yu

    (University of Michigan)

  • Bokai Zhang

    (University of Michigan)

  • Jianchao Zhang

    (University of Michigan)

  • Woo Jung Cho

    (University of Michigan Medical School)

  • Varsha Venkatarangan

    (University of Michigan)

  • Liang Chen

    (University of Michigan)

  • Bala Bharathi Burugula

    (University of Michigan Medical School)

  • Sarah Bui

    (University of Michigan)

  • Yanzhuang Wang

    (University of Michigan)

  • Cunming Duan

    (University of Michigan)

  • Jacob O. Kitzman

    (University of Michigan Medical School)

  • Ming Li

    (University of Michigan)

Abstract

The mannose-6-phosphate (M6P) biosynthetic pathway for lysosome biogenesis has been studied for decades and is considered a well-understood topic. However, whether this pathway is regulated remains an open question. In a genome-wide CRISPR/Cas9 knockout screen, we discover TMEM251 as the first regulator of the M6P modification. Deleting TMEM251 causes mistargeting of most lysosomal enzymes due to their loss of M6P modification and accumulation of numerous undigested materials. We further demonstrate that TMEM251 localizes to the Golgi and is required for the cleavage and activity of GNPT, the enzyme that catalyzes M6P modification. In zebrafish, TMEM251 deletion leads to severe developmental defects including heart edema and skeletal dysplasia, which phenocopies Mucolipidosis Type II. Our discovery provides a mechanism for the newly discovered human disease caused by TMEM251 mutations. We name TMEM251 as GNPTAB cleavage and activity factor (GCAF) and its related disease as Mucolipidosis Type V.

Suggested Citation

  • Weichao Zhang & Xi Yang & Yingxiang Li & Linchen Yu & Bokai Zhang & Jianchao Zhang & Woo Jung Cho & Varsha Venkatarangan & Liang Chen & Bala Bharathi Burugula & Sarah Bui & Yanzhuang Wang & Cunming Du, 2022. "GCAF(TMEM251) regulates lysosome biogenesis by activating the mannose-6-phosphate pathway," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33025-1
    DOI: 10.1038/s41467-022-33025-1
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    References listed on IDEAS

    as
    1. Yingyao Zhou & Bin Zhou & Lars Pache & Max Chang & Alireza Hadj Khodabakhshi & Olga Tanaseichuk & Christopher Benner & Sumit K. Chanda, 2019. "Metascape provides a biologist-oriented resource for the analysis of systems-level datasets," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
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    Cited by:

    1. Vincent El Ghouzzi & Gaelle Boncompain, 2022. "Golgipathies reveal the critical role of the sorting machinery in brain and skeletal development," Nature Communications, Nature, vol. 13(1), pages 1-4, December.

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