{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T13:57:08Z","timestamp":1782914228988,"version":"3.54.5"},"reference-count":32,"publisher":"American Society for Microbiology","license":[{"start":{"date-parts":[[2023,7,21]],"date-time":"2023-07-21T00:00:00Z","timestamp":1689897600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2023,7,21]],"date-time":"2023-07-21T00:00:00Z","timestamp":1689897600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"HHS | National Institutes of Health","award":["AI59945"],"award-info":[{"award-number":["AI59945"]}]},{"name":"The Walder Foundation","award":["Chicago Coronavirus Assessment Network (Chicago CAN)"],"award-info":[{"award-number":["Chicago Coronavirus Assessment Network (Chicago CAN)"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>We recently reported that mutations in both the spike glycoprotein and nonstructural protein 6 (nsp6) were associated with attenuation of the SARS-CoV-2 Omicron BA.1 variant. While mutations in spike allow evasion of neutralizing antibodies and promote specific modes of viral entry, the role of nsp6 mutations in pathogenesis is less clear. Nsp6 is essential for modifying the endoplasmic reticulum and generating double-membrane vesicles, the site of viral RNA replication. To investigate the evolution of nsp6, we evaluated 91,596 high-confidence human SARS-CoV-2 whole-genome sequences across 19 variants and lineages. While nsp6 of early variants of concern, such as Alpha, Beta, and Gamma, carried a triple amino acid deletion (106\u2013108, termed \u0394SGF), the Delta, Epsilon, and Mu lineages retained the ancestral nsp6 sequence. For nsp6 in the emerging Omicron variants, we report a transition from an amino acid 105\u2013107 \u0394LSG deletion in BA.1 to increased dominance of the \u0394SGF in BA.2 and subsequent lineages. Our findings indicate that deletion within nsp6 was independently selected in multiple lineages of SARS-CoV-2, both early and late in the pandemic. Analysis of SARS-CoV-2-related coronaviruses in bats and pangolins revealed nsp6 sequences similar to the ancestral SARS-CoV-2 virus, indicating that the deletion in nsp6 may be an adaptation to replication in humans. Analysis of nsp6 sequences from multiple coronaviruses predicts a multipass transmembrane protein with a conserved C-terminal domain. Monitoring and evaluating changes in nsp6 and other nonstructural proteins will contribute to our understanding of factors associated with the attenuation of pandemic coronaviruses.<\/jats:p>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              There is an ongoing need to evaluate genetic changes in SARS-CoV-2 for effects on transmission and pathogenesis. We recently reported an unexpected role for replicase component nsp6, in addition to changes in spike, in the attenuation of Omicron BA.1. In this commentary, we document a triple-amino-acid deletion in a predicted lumenal domain of nsp6 that was found in multiple, independent variants of SARS-CoV-2, including all recent Omicron lineages. Furthermore, we modeled the predicted structure of nsp6, implicating a multipass transmembrane architecture as conserved in members of the\n              <jats:italic>Coronaviridae<\/jats:italic>\n              family. This information can guide future studies investigating the role of nsp6 in the pathogenesis of existing and emerging coronaviruses.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/mbio.00688-23","type":"journal-article","created":{"date-parts":[[2023,7,21]],"date-time":"2023-07-21T13:00:44Z","timestamp":1689944444000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":13,"title":["SARS-CoV-2 nonstructural protein 6 from Alpha to Omicron: evolution of a transmembrane protein"],"prefix":"10.1128","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8878-8036","authenticated-orcid":true,"given":"Shuchen","family":"Feng","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago , Chicago, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amornrat","family":"O'Brien","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago , Chicago, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da-Yuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cell Biology, Boston University Chobanian and Avedisian School of Medicine , Boston, Massachusetts, USA"},{"name":"National Emerging Infectious Diseases Laboratories (NEIDL) , Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8505-7054","authenticated-orcid":true,"given":"Mohsan","family":"Saeed","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cell Biology, Boston University Chobanian and Avedisian School of Medicine , Boston, Massachusetts, USA"},{"name":"National Emerging Infectious Diseases Laboratories (NEIDL) , Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6485-8143","authenticated-orcid":true,"given":"Susan C.","family":"Baker","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago , Chicago, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","published-online":{"date-parts":[[2023,7,21]]},"reference":[{"key":"e_1_3_3_2_2","unstructured":"Centers for Disease Control and Prevention\n. 2023. SARS-CoV-2 variant classifications and definitions. Available from: https:\/\/www.cdc.gov\/coronavirus\/2019-ncov\/variants\/variant-classifications.html"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-021-00573-0"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-021-00418-x"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abl6184"},{"key":"e_1_3_3_6_2","unstructured":"World Health Organization (WHO)\n. 2021 Classification of Omicron (B.1.1.529): SARS-CoV-2 variant of concern. Available from: https:\/\/www.who.int\/news\/item\/26-11-2021-classification-of-omicron-(b.1.1.529)-sars-cov-2-variant-of-concern"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04441-6"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.ade1860"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)00462-7"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-01887-z"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiad236"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-05697-2"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-37787-0"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0060226"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00524-13"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2020.12.007"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01219-08"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.76.8.3697-3708.2002"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000715"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2020.11.003"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.110049"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04835-6"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.5808\/GI.2020.18.4.e44"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.11.020"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21768-2"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.06.008"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05048-7"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2012-7"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00254-09"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/17.9.849"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/14.4.378"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2004.03.016"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.2000.4315"}],"container-title":["mBio"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mbio.00688-23","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mbio.00688-23","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,21]],"date-time":"2023-07-21T13:00:54Z","timestamp":1689944454000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/mbio.00688-23"}},"subtitle":[],"editor":[{"given":"J. S. Malik","family":"Peiris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,7,21]]},"references-count":32,"alternative-id":["10.1128\/mbio.00688-23"],"URL":"https:\/\/doi.org\/10.1128\/mbio.00688-23","relation":{},"ISSN":["2150-7511"],"issn-type":[{"value":"2150-7511","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,21]]},"assertion":[{"value":"2023-03-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-06-10","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-07-21","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00688-23"}}