LRRC15 mediates an accessory interaction with the SARS-CoV-2 spike protein
The interactions between Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and human host factors enable the virus to propagate infections that lead to Coronavirus Disease 2019 (COVID-19). The spike protein is the largest structural component of the virus and mediates interactions essenti...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-02-01
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| Series: | PLoS Biology |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9897555/?tool=EBI |
| _version_ | 1811170953817751552 |
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| author | Jarrod Shilts Thomas W. M. Crozier Ana Teixeira-Silva Ildar Gabaev Pehuén Pereyra Gerber Edward J. D. Greenwood Samuel James Watson Brian M. Ortmann Christian M. Gawden-Bone Tekle Pauzaite Markus Hoffmann James A. Nathan Stefan Pöhlmann Nicholas J. Matheson Paul J. Lehner Gavin J. Wright |
| author_facet | Jarrod Shilts Thomas W. M. Crozier Ana Teixeira-Silva Ildar Gabaev Pehuén Pereyra Gerber Edward J. D. Greenwood Samuel James Watson Brian M. Ortmann Christian M. Gawden-Bone Tekle Pauzaite Markus Hoffmann James A. Nathan Stefan Pöhlmann Nicholas J. Matheson Paul J. Lehner Gavin J. Wright |
| author_sort | Jarrod Shilts |
| collection | DOAJ |
| description | The interactions between Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and human host factors enable the virus to propagate infections that lead to Coronavirus Disease 2019 (COVID-19). The spike protein is the largest structural component of the virus and mediates interactions essential for infection, including with the primary angiotensin-converting enzyme 2 (ACE2) receptor. We performed two independent cell-based systematic screens to determine whether there are additional proteins by which the spike protein of SARS-CoV-2 can interact with human cells. We discovered that in addition to ACE2, expression of LRRC15 also causes spike protein binding. This interaction is distinct from other known spike attachment mechanisms such as heparan sulfates or lectin receptors. Measurements of orthologous coronavirus spike proteins implied the interaction was functionally restricted to SARS-CoV-2 by accessibility. We localized the interaction to the C-terminus of the S1 domain and showed that LRRC15 shares recognition of the ACE2 receptor binding domain. From analyzing proteomics and single-cell transcriptomics, we identify LRRC15 expression as being common in human lung vasculature cells and fibroblasts. Levels of LRRC15 were greatly elevated by inflammatory signals in the lungs of COVID-19 patients. Although infection assays demonstrated that LRRC15 alone is not sufficient to permit viral entry, we present evidence that it can modulate infection of human cells. This unexpected interaction merits further investigation to determine how SARS-CoV-2 exploits host LRRC15 and whether it could account for any of the distinctive features of COVID-19. A systematic search for human proteins that can bind to the spike protein of SARS-CoV-2 reveals that LRRC15 can act as a host factor for the virus, and may therefore modulate infection with potential implications for COVID-19. |
| first_indexed | 2024-04-10T17:05:23Z |
| format | Article |
| id | doaj.art-90f98ee96aff4b489c474fa416cf8b43 |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-04-10T17:05:23Z |
| publishDate | 2023-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-90f98ee96aff4b489c474fa416cf8b432023-02-06T05:30:38ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852023-02-01212LRRC15 mediates an accessory interaction with the SARS-CoV-2 spike proteinJarrod ShiltsThomas W. M. CrozierAna Teixeira-SilvaIldar GabaevPehuén Pereyra GerberEdward J. D. GreenwoodSamuel James WatsonBrian M. OrtmannChristian M. Gawden-BoneTekle PauzaiteMarkus HoffmannJames A. NathanStefan PöhlmannNicholas J. MathesonPaul J. LehnerGavin J. WrightThe interactions between Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and human host factors enable the virus to propagate infections that lead to Coronavirus Disease 2019 (COVID-19). The spike protein is the largest structural component of the virus and mediates interactions essential for infection, including with the primary angiotensin-converting enzyme 2 (ACE2) receptor. We performed two independent cell-based systematic screens to determine whether there are additional proteins by which the spike protein of SARS-CoV-2 can interact with human cells. We discovered that in addition to ACE2, expression of LRRC15 also causes spike protein binding. This interaction is distinct from other known spike attachment mechanisms such as heparan sulfates or lectin receptors. Measurements of orthologous coronavirus spike proteins implied the interaction was functionally restricted to SARS-CoV-2 by accessibility. We localized the interaction to the C-terminus of the S1 domain and showed that LRRC15 shares recognition of the ACE2 receptor binding domain. From analyzing proteomics and single-cell transcriptomics, we identify LRRC15 expression as being common in human lung vasculature cells and fibroblasts. Levels of LRRC15 were greatly elevated by inflammatory signals in the lungs of COVID-19 patients. Although infection assays demonstrated that LRRC15 alone is not sufficient to permit viral entry, we present evidence that it can modulate infection of human cells. This unexpected interaction merits further investigation to determine how SARS-CoV-2 exploits host LRRC15 and whether it could account for any of the distinctive features of COVID-19. A systematic search for human proteins that can bind to the spike protein of SARS-CoV-2 reveals that LRRC15 can act as a host factor for the virus, and may therefore modulate infection with potential implications for COVID-19.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9897555/?tool=EBI |
| spellingShingle | Jarrod Shilts Thomas W. M. Crozier Ana Teixeira-Silva Ildar Gabaev Pehuén Pereyra Gerber Edward J. D. Greenwood Samuel James Watson Brian M. Ortmann Christian M. Gawden-Bone Tekle Pauzaite Markus Hoffmann James A. Nathan Stefan Pöhlmann Nicholas J. Matheson Paul J. Lehner Gavin J. Wright LRRC15 mediates an accessory interaction with the SARS-CoV-2 spike protein PLoS Biology |
| title | LRRC15 mediates an accessory interaction with the SARS-CoV-2 spike protein |
| title_full | LRRC15 mediates an accessory interaction with the SARS-CoV-2 spike protein |
| title_fullStr | LRRC15 mediates an accessory interaction with the SARS-CoV-2 spike protein |
| title_full_unstemmed | LRRC15 mediates an accessory interaction with the SARS-CoV-2 spike protein |
| title_short | LRRC15 mediates an accessory interaction with the SARS-CoV-2 spike protein |
| title_sort | lrrc15 mediates an accessory interaction with the sars cov 2 spike protein |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9897555/?tool=EBI |
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