The human disease gene LYSET is essential for lysosomal enzyme transport and viral infection
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). Seve...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2022-10, Vol.378 (6615), p.eabn5648-eabn5648 |
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| creator | Richards, Christopher M Jabs, Sabrina Qiao, Wenjie Varanese, Lauren D Schweizer, Michaela Mosen, Peter R Riley, Nicholas M Klüssendorf, Malte Zengel, James R Flynn, Ryan A Rustagi, Arjun Widen, John C Peters, Christine E Ooi, Yaw Shin Xie, Xuping Shi, Pei-Yong Bartenschlager, Ralf Puschnik, Andreas S Bogyo, Matthew Bertozzi, Carolyn R Blish, Catherine A Winter, Dominic Nagamine, Claude M Braulke, Thomas Carette, Jan E |
| description | 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.
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. |
| doi_str_mv | 10.1126/science.abn5648 |
| format | Article |
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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.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.abn5648</identifier><identifier>PMID: 36074821</identifier><language>eng</language><publisher>United States: The American Association for the Advancement of Science</publisher><subject>Accumulation ; Amino acids ; Animals ; Biosynthesis ; Cathepsins ; Cathepsins - metabolism ; Compartments ; Complementation ; Coronaviruses ; COVID-19 ; COVID-19 - genetics ; Critical components ; Cytoplasm ; Defects ; Degradation ; Disorders ; DNA probes ; Ebola virus ; Ebolavirus ; Enzymes ; Evolution ; Genetic Disorders ; Genetic screening ; Genomes ; Glycoproteins ; Golgi apparatus ; Hereditary diseases ; Homeostasis ; Humans ; Infections ; Intracellular ; Localization ; Lysosomal enzymes ; Lysosomal storage diseases ; Lysosomes ; Lysosomes - metabolism ; Mannose ; Mannose - metabolism ; Marking ; Mice ; Mice, Knockout ; Mucolipidoses - genetics ; Mucolipidoses - metabolism ; Mucolipidosis ; Mutation ; N-Acetylglucosamine ; Phosphotransferase ; Proteins ; Proteins - genetics ; Proteomics ; Respiratory diseases ; Severe acute respiratory syndrome ; Severe acute respiratory syndrome coronavirus 2 ; Signs and symptoms ; Stomatitis ; Structural proteins ; Transferases (Other Substituted Phosphate Groups) ; Viral diseases ; Viral infections ; Viruses</subject><ispartof>Science (American Association for the Advancement of Science), 2022-10, Vol.378 (6615), p.eabn5648-eabn5648</ispartof><rights>Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c421t-6a0b7b0161cf666532d3ef820b8df065bce17ff23a53f1510e075820e8ca9d943</citedby><cites>FETCH-LOGICAL-c421t-6a0b7b0161cf666532d3ef820b8df065bce17ff23a53f1510e075820e8ca9d943</cites><orcidid>0000-0002-1536-2966 ; 0000-0003-0918-016X ; 0000-0002-5187-8070 ; 0000-0002-9605-9458 ; 0000-0001-5013-0442 ; 0000-0003-0832-8951 ; 0000-0001-6946-7627 ; 0000-0002-6921-1012 ; 0000-0001-8065-8002 ; 0000-0003-3753-4412 ; 0000-0001-9014-1365 ; 0000-0001-6788-6641 ; 0000-0003-3153-3603 ; 0000-0001-5922-3805 ; 0000-0001-6790-8951 ; 0000-0003-3916-8401 ; 0000-0002-2336-8532 ; 0000-0001-7450-607X ; 0000-0002-8973-1509 ; 0000-0002-0255-6155 ; 0000-0001-5062-328X ; 0000-0003-4482-2754 ; 0000-0003-0392-4383 ; 0000-0001-5553-1616 ; 0000-0002-9568-6206</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,2871,2872,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36074821$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Richards, Christopher M</creatorcontrib><creatorcontrib>Jabs, Sabrina</creatorcontrib><creatorcontrib>Qiao, Wenjie</creatorcontrib><creatorcontrib>Varanese, Lauren D</creatorcontrib><creatorcontrib>Schweizer, Michaela</creatorcontrib><creatorcontrib>Mosen, Peter R</creatorcontrib><creatorcontrib>Riley, Nicholas M</creatorcontrib><creatorcontrib>Klüssendorf, Malte</creatorcontrib><creatorcontrib>Zengel, James R</creatorcontrib><creatorcontrib>Flynn, Ryan A</creatorcontrib><creatorcontrib>Rustagi, Arjun</creatorcontrib><creatorcontrib>Widen, John C</creatorcontrib><creatorcontrib>Peters, Christine E</creatorcontrib><creatorcontrib>Ooi, Yaw Shin</creatorcontrib><creatorcontrib>Xie, Xuping</creatorcontrib><creatorcontrib>Shi, Pei-Yong</creatorcontrib><creatorcontrib>Bartenschlager, Ralf</creatorcontrib><creatorcontrib>Puschnik, Andreas S</creatorcontrib><creatorcontrib>Bogyo, Matthew</creatorcontrib><creatorcontrib>Bertozzi, Carolyn R</creatorcontrib><creatorcontrib>Blish, Catherine A</creatorcontrib><creatorcontrib>Winter, Dominic</creatorcontrib><creatorcontrib>Nagamine, Claude M</creatorcontrib><creatorcontrib>Braulke, Thomas</creatorcontrib><creatorcontrib>Carette, Jan E</creatorcontrib><title>The human disease gene LYSET is essential for lysosomal enzyme transport and viral infection</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>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.
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.</description><subject>Accumulation</subject><subject>Amino acids</subject><subject>Animals</subject><subject>Biosynthesis</subject><subject>Cathepsins</subject><subject>Cathepsins - metabolism</subject><subject>Compartments</subject><subject>Complementation</subject><subject>Coronaviruses</subject><subject>COVID-19</subject><subject>COVID-19 - genetics</subject><subject>Critical components</subject><subject>Cytoplasm</subject><subject>Defects</subject><subject>Degradation</subject><subject>Disorders</subject><subject>DNA probes</subject><subject>Ebola virus</subject><subject>Ebolavirus</subject><subject>Enzymes</subject><subject>Evolution</subject><subject>Genetic Disorders</subject><subject>Genetic screening</subject><subject>Genomes</subject><subject>Glycoproteins</subject><subject>Golgi apparatus</subject><subject>Hereditary diseases</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Infections</subject><subject>Intracellular</subject><subject>Localization</subject><subject>Lysosomal enzymes</subject><subject>Lysosomal storage diseases</subject><subject>Lysosomes</subject><subject>Lysosomes - metabolism</subject><subject>Mannose</subject><subject>Mannose - metabolism</subject><subject>Marking</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Mucolipidoses - genetics</subject><subject>Mucolipidoses - metabolism</subject><subject>Mucolipidosis</subject><subject>Mutation</subject><subject>N-Acetylglucosamine</subject><subject>Phosphotransferase</subject><subject>Proteins</subject><subject>Proteins - genetics</subject><subject>Proteomics</subject><subject>Respiratory diseases</subject><subject>Severe acute respiratory syndrome</subject><subject>Severe acute respiratory syndrome coronavirus 2</subject><subject>Signs and 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John C</au><au>Peters, Christine E</au><au>Ooi, Yaw Shin</au><au>Xie, Xuping</au><au>Shi, Pei-Yong</au><au>Bartenschlager, Ralf</au><au>Puschnik, Andreas S</au><au>Bogyo, Matthew</au><au>Bertozzi, Carolyn R</au><au>Blish, Catherine A</au><au>Winter, Dominic</au><au>Nagamine, Claude M</au><au>Braulke, Thomas</au><au>Carette, Jan E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The human disease gene LYSET is essential for lysosomal enzyme transport and viral infection</atitle><jtitle>Science (American Association for the Advancement of Science)</jtitle><addtitle>Science</addtitle><date>2022-10-07</date><risdate>2022</risdate><volume>378</volume><issue>6615</issue><spage>eabn5648</spage><epage>eabn5648</epage><pages>eabn5648-eabn5648</pages><issn>0036-8075</issn><eissn>1095-9203</eissn><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.
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.</abstract><cop>United States</cop><pub>The American Association for the Advancement of Science</pub><pmid>36074821</pmid><doi>10.1126/science.abn5648</doi><orcidid>https://orcid.org/0000-0002-1536-2966</orcidid><orcidid>https://orcid.org/0000-0003-0918-016X</orcidid><orcidid>https://orcid.org/0000-0002-5187-8070</orcidid><orcidid>https://orcid.org/0000-0002-9605-9458</orcidid><orcidid>https://orcid.org/0000-0001-5013-0442</orcidid><orcidid>https://orcid.org/0000-0003-0832-8951</orcidid><orcidid>https://orcid.org/0000-0001-6946-7627</orcidid><orcidid>https://orcid.org/0000-0002-6921-1012</orcidid><orcidid>https://orcid.org/0000-0001-8065-8002</orcidid><orcidid>https://orcid.org/0000-0003-3753-4412</orcidid><orcidid>https://orcid.org/0000-0001-9014-1365</orcidid><orcidid>https://orcid.org/0000-0001-6788-6641</orcidid><orcidid>https://orcid.org/0000-0003-3153-3603</orcidid><orcidid>https://orcid.org/0000-0001-5922-3805</orcidid><orcidid>https://orcid.org/0000-0001-6790-8951</orcidid><orcidid>https://orcid.org/0000-0003-3916-8401</orcidid><orcidid>https://orcid.org/0000-0002-2336-8532</orcidid><orcidid>https://orcid.org/0000-0001-7450-607X</orcidid><orcidid>https://orcid.org/0000-0002-8973-1509</orcidid><orcidid>https://orcid.org/0000-0002-0255-6155</orcidid><orcidid>https://orcid.org/0000-0001-5062-328X</orcidid><orcidid>https://orcid.org/0000-0003-4482-2754</orcidid><orcidid>https://orcid.org/0000-0003-0392-4383</orcidid><orcidid>https://orcid.org/0000-0001-5553-1616</orcidid><orcidid>https://orcid.org/0000-0002-9568-6206</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0036-8075 |
| ispartof | Science (American Association for the Advancement of Science), 2022-10, Vol.378 (6615), p.eabn5648-eabn5648 |
| issn | 0036-8075 1095-9203 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9547973 |
| source | MEDLINE; Science Magazine |
| subjects | Accumulation Amino acids Animals Biosynthesis Cathepsins Cathepsins - metabolism Compartments Complementation Coronaviruses COVID-19 COVID-19 - genetics Critical components Cytoplasm Defects Degradation Disorders DNA probes Ebola virus Ebolavirus Enzymes Evolution Genetic Disorders Genetic screening Genomes Glycoproteins Golgi apparatus Hereditary diseases Homeostasis Humans Infections Intracellular Localization Lysosomal enzymes Lysosomal storage diseases Lysosomes Lysosomes - metabolism Mannose Mannose - metabolism Marking Mice Mice, Knockout Mucolipidoses - genetics Mucolipidoses - metabolism Mucolipidosis Mutation N-Acetylglucosamine Phosphotransferase Proteins Proteins - genetics Proteomics Respiratory diseases Severe acute respiratory syndrome Severe acute respiratory syndrome coronavirus 2 Signs and symptoms Stomatitis Structural proteins Transferases (Other Substituted Phosphate Groups) Viral diseases Viral infections Viruses |
| title | The human disease gene LYSET is essential for lysosomal enzyme transport and viral infection |
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