2. Academic Validation
  3. The human disease gene LYSET is essential for lysosomal enzyme transport and viral infection

The human disease gene LYSET is essential for lysosomal enzyme transport and viral infection

  • Science. 2022 Oct 7;378(6615):eabn5648. doi: 10.1126/science.abn5648.
Christopher M Richards # 1,  Sabrina Jabs # 2,  Wenjie Qiao # 1,  Lauren D Varanese 1,  Michaela Schweizer 3,  Peter R Mosen 4,  Nicholas M Riley 5,  Malte Klüssendorf 6,  James R Zengel 1,  Ryan A Flynn 7 8,  Arjun Rustagi 9,  John C Widen 10,  Christine E Peters 1,  Yaw Shin Ooi 11,  Xuping Xie 12,  Pei-Yong Shi 12,  Ralf Bartenschlager 13 14,  Andreas S Puschnik 15,  Matthew Bogyo 1 10,  Carolyn R Bertozzi 5 16,  Catherine A Blish 9,  Dominic Winter 4,  Claude M Nagamine 17,  Thomas Braulke 6,  Jan E Carette 1
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
  • 2 Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany.
  • 3 Department of Electron Microscopy, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 4 Institute for Biochemistry and Molecular Biology, Medical Faculty, Rheinische Friedrich-Wilhelms-University of Bonn, Bonn, Germany.
  • 5 Department of Chemistry, Stanford University, Stanford, CA, USA.
  • 6 Department of Osteology and Biomechanics, Cell Biology of Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 7 Stem Cell Program, Boston Children's Hospital, Boston, MA, USA.
  • 8 Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA, USA.
  • 9 Division of Infectious Disease and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
  • 10 Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  • 11 Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore.
  • 12 Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.
  • 13 Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany.
  • 14 Division Virus-Associated Carcinogenesis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 15 Chan Zuckerberg Biohub, San Francisco, CA, USA.
  • 16 Howard Hughes Medical Institute, Stanford, CA, USA.
  • 17 Department of Comparative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
  • # Contributed equally.
PMID: 36074821 DOI: 10.1126/science.abn5648
Abstract

Lysosomes are key degradative compartments of the cell. Transport to lysosomes relies on GlcNAc-1-phosphotransferase-mediated tagging of soluble enzymes with mannose 6-phosphate (M6P). GlcNAc-1-phosphotransferase deficiency leads to the severe lysosomal storage disorder mucolipidosis II (MLII). Several viruses require lysosomal cathepsins to cleave structural proteins and thus depend on functional GlcNAc-1-phosphotransferase. We used genome-scale CRISPR screens to identify lysosomal Enzyme trafficking factor (LYSET, also named TMEM251) as essential for Infection by cathepsin-dependent viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). LYSET deficiency resulted in global loss of M6P tagging and mislocalization of GlcNAc-1-phosphotransferase from the Golgi complex to lysosomes. Lyset knockout mice exhibited MLII-like phenotypes, and human pathogenic LYSET alleles failed to restore lysosomal sorting defects. Thus, LYSET is required for correct functioning of the M6P trafficking machinery and mutations in LYSET can explain the phenotype of the associated disorder.

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