Contribution of Syndecans to the Cellular Entry of SARS-CoV-2
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel emerging pathogen causing an unprecedented pandemic in 21st century medicine. Due to the significant health and economic burden of the current SARS-CoV-2 outbreak, there is a huge unmet medical need for novel interventions e...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-05-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/10/5336 |
| _version_ | 1797533535496568832 |
|---|---|
| author | Anett Hudák Annamária Letoha László Szilák Tamás Letoha |
| author_facet | Anett Hudák Annamária Letoha László Szilák Tamás Letoha |
| author_sort | Anett Hudák |
| collection | DOAJ |
| description | The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel emerging pathogen causing an unprecedented pandemic in 21st century medicine. Due to the significant health and economic burden of the current SARS-CoV-2 outbreak, there is a huge unmet medical need for novel interventions effectively blocking SARS-CoV-2 infection. Unknown details of SARS-CoV-2 cellular biology hamper the development of potent and highly specific SARS-CoV-2 therapeutics. Angiotensin-converting enzyme-2 (ACE2) has been reported to be the primary receptor for SARS-CoV-2 cellular entry. However, emerging scientific evidence suggests the involvement of additional membrane proteins, such as heparan sulfate proteoglycans, in SARS-CoV-2 internalization. Here, we report that syndecans, the evolutionarily conserved family of transmembrane proteoglycans, facilitate the cellular entry of SARS-CoV-2. Among syndecans, the lung abundant syndecan-4 was the most efficient in mediating SARS-CoV-2 uptake. The S1 subunit of the SARS-CoV-2 spike protein plays a dominant role in the virus’s interactions with syndecans. Besides the polyanionic heparan sulfate chains, other parts of the syndecan ectodomain, such as the cell-binding domain, also contribute to the interaction with SARS-CoV-2. During virus internalization, syndecans colocalize with ACE2, suggesting a jointly shared internalization pathway. Both ACE2 and syndecan inhibitors exhibited significant efficacy in reducing the cellular entry of SARS-CoV-2, thus supporting the complex nature of internalization. Data obtained on syndecan specific in vitro assays present syndecans as novel cellular targets of SARS-CoV-2 and offer molecularly precise yet simple strategies to overcome the complex nature of SARS-CoV-2 infection. |
| first_indexed | 2024-03-10T11:15:57Z |
| format | Article |
| id | doaj.art-35e9b58564f542c39ee4ffb0380bdc5a |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T11:15:57Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-35e9b58564f542c39ee4ffb0380bdc5a2023-11-21T20:23:01ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-05-012210533610.3390/ijms22105336Contribution of Syndecans to the Cellular Entry of SARS-CoV-2Anett Hudák0Annamária Letoha1László Szilák2Tamás Letoha3Pharmacoidea Ltd., H-6726 Szeged, HungaryDepartment of Medicine, Albert Szent-Györgyi Clinical Center, Faculty of Medicine, University of Szeged, H-6725 Szeged, HungaryPharmacoidea Ltd., H-6726 Szeged, HungaryPharmacoidea Ltd., H-6726 Szeged, HungaryThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel emerging pathogen causing an unprecedented pandemic in 21st century medicine. Due to the significant health and economic burden of the current SARS-CoV-2 outbreak, there is a huge unmet medical need for novel interventions effectively blocking SARS-CoV-2 infection. Unknown details of SARS-CoV-2 cellular biology hamper the development of potent and highly specific SARS-CoV-2 therapeutics. Angiotensin-converting enzyme-2 (ACE2) has been reported to be the primary receptor for SARS-CoV-2 cellular entry. However, emerging scientific evidence suggests the involvement of additional membrane proteins, such as heparan sulfate proteoglycans, in SARS-CoV-2 internalization. Here, we report that syndecans, the evolutionarily conserved family of transmembrane proteoglycans, facilitate the cellular entry of SARS-CoV-2. Among syndecans, the lung abundant syndecan-4 was the most efficient in mediating SARS-CoV-2 uptake. The S1 subunit of the SARS-CoV-2 spike protein plays a dominant role in the virus’s interactions with syndecans. Besides the polyanionic heparan sulfate chains, other parts of the syndecan ectodomain, such as the cell-binding domain, also contribute to the interaction with SARS-CoV-2. During virus internalization, syndecans colocalize with ACE2, suggesting a jointly shared internalization pathway. Both ACE2 and syndecan inhibitors exhibited significant efficacy in reducing the cellular entry of SARS-CoV-2, thus supporting the complex nature of internalization. Data obtained on syndecan specific in vitro assays present syndecans as novel cellular targets of SARS-CoV-2 and offer molecularly precise yet simple strategies to overcome the complex nature of SARS-CoV-2 infection.https://www.mdpi.com/1422-0067/22/10/5336coronavirusesSARS-CoV-2spike proteincellular entrysyndecans |
| spellingShingle | Anett Hudák Annamária Letoha László Szilák Tamás Letoha Contribution of Syndecans to the Cellular Entry of SARS-CoV-2 International Journal of Molecular Sciences coronaviruses SARS-CoV-2 spike protein cellular entry syndecans |
| title | Contribution of Syndecans to the Cellular Entry of SARS-CoV-2 |
| title_full | Contribution of Syndecans to the Cellular Entry of SARS-CoV-2 |
| title_fullStr | Contribution of Syndecans to the Cellular Entry of SARS-CoV-2 |
| title_full_unstemmed | Contribution of Syndecans to the Cellular Entry of SARS-CoV-2 |
| title_short | Contribution of Syndecans to the Cellular Entry of SARS-CoV-2 |
| title_sort | contribution of syndecans to the cellular entry of sars cov 2 |
| topic | coronaviruses SARS-CoV-2 spike protein cellular entry syndecans |
| url | https://www.mdpi.com/1422-0067/22/10/5336 |
| work_keys_str_mv | AT anetthudak contributionofsyndecanstothecellularentryofsarscov2 AT annamarialetoha contributionofsyndecanstothecellularentryofsarscov2 AT laszloszilak contributionofsyndecanstothecellularentryofsarscov2 AT tamasletoha contributionofsyndecanstothecellularentryofsarscov2 |