@article{11ae4475f1b74903ad87ea53ce3d3d07,
title = "The human disease gene LYSET is essential for lysosomal enzyme transport and viral infection",
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.",
author = "Richards, {Christopher M.} and Sabrina Jabs and Wenjie Qiao and Varanese, {Lauren D.} and Michaela Schweizer and Mosen, {Peter R.} and Riley, {Nicholas M.} and Malte Kl{\"u}ssendorf and Zengel, {James R.} and Flynn, {Ryan A.} and Arjun Rustagi and Widen, {John C.} and Peters, {Christine E.} and Ooi, {Yaw Shin} and Xuping Xie and Shi, {Pei Yong} and Ralf Bartenschlager and Puschnik, {Andreas S.} and Matthew Bogyo and Bertozzi, {Carolyn R.} and Blish, {Catherine A.} and Dominic Winter and Nagamine, {Claude M.} and Thomas Braulke and Carette, {Jan E.}",
note = "Funding Information: The authors thank A. Dupzyk, B. Waldman, A. Johnson, and C. LaPointe for insightful comments. We thank M. Bassik and D. Monack for access to their respective Incucyte microscopes, E. Szpotowicz, C. Raithore, and J. Rehberg for technical assistance, and R. Hardt for support with DIA and PRM data analysis and visualization. We thank F. Seyfried, G. Dubberke, F. Koch-Nolte, and Institute of Immunology, UKE, Hamburg, for assistance with the production of mAb RG95-A96. We thank W. Palm for sharing unpublished data. Some images were created with BioRender.com. This work was funded in part by the National Institutes of Health (NIH) T32 AI007502 (to C.M.R.); NIH T32 GM007276 (to L.D.V.); NIH T32 AI007502 (to A.R.); NIH R01 AI140186 (to J.E.C.); NIH R01 AI141970 (to J.E.C.); NIH R01 AI130123 (to J.E.C.); NIH R01 GM058867 (to C.R.B.); NIH R01 AI134907 (to P.-Y.S); NIH K00CA21245 (to N.M.R.); Deutsche Forschungsgemeinschaft (DFG) CRC877 (to T.B. and M.S.); DFG FOR2625 TP7 (to P.R.M., D.W., and T.B.); DFG 240245660-SFB1129 (to R.B.); DFG 272983813-TRR 179 (to R.B.); Helmholtz Association's Initiative and Networking Fund KA1-Co-02 “COVIPA” (to R.B.); Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Disease (to J.E.C.); Stanford ChEM-H Innovative Medicines Accelerator (to J.E.C); Sealy Smith Foundation (to P.-Y.S); Kleberg Foundation (to P.-Y.S); John S. Dunn Foundation (to P.-Y.S); Amon G. Carter Foundation (to P.-Y.S); Gillson Longenbaugh Foundation (to P.-Y.S); and Summerfield Robert Foundation (to P.-Y.S). Publisher Copyright: Copyright {\textcopyright} 2022 The Authors, some rights reserved.",
year = "2022",
month = oct,
day = "7",
doi = "10.1126/science.abn5648",
language = "English (US)",
volume = "378",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6615",
}