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SARS-CoV-2 Nsp14 binds Tollip and activates pro-inflammatory pathways while downregulating interferon-α and interferon-γ receptors

Thakur et al., mBio, doi:10.1128/mbio.01071-25, Aug 2025
https://c19early.org/thakur.html
In Vitro study showing that SARS-CoV-2 Nsp14 protein activates pro-inflammatory pathways while simultaneously downregulating interferon receptors, with the host protein Tollip serving as a potential regulator of these effects.
Thakur et al., 13 Aug 2025, peer-reviewed, 4 authors. Contact: chris.basler@mssm.edu, joann.tufariello@mssm.edu.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
SARS-CoV-2 Nsp14 binds Tollip and activates pro-inflammatory pathways while downregulating interferon-α and interferon-γ receptors
Naveen Thakur, Poushali Chakraborty, Joann M Tufariello, Christopher F Basler
mBio, doi:10.1128/mbio.01071-25
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) non-struc tural protein 14 (Nsp14) possesses an N-terminal exonuclease (ExoN) domain that provides a proofreading function for the viral RNA-dependent RNA polymerase and a C-terminal N7-methyltransferase (N7-MTase) domain that methylates viral mRNA caps. Nsp14 also modulates host functions. This includes the activation of NF-κB and downregulation of interferon alpha/beta receptor 1 (IFNAR1). Here, we demonstrate that Nsp14 exerts broader effects, activating not only NF-κB responses but also extracellu lar-signal-regulated kinase (ERK), p38, and Jun amino-terminal kinase (JNK) mitogen-acti vated protein kinase (MAPK) signaling, promoting cytokine production. Furthermore, Nsp14 downregulates not only IFNAR1 but also IFN-γ receptor 1 (IFNGR1), impairing cellular responses to both IFNα and IFNγ. IFNAR1 and IFNGR1 downregulation is via a lysosomal pathway and occurs in SARS-CoV-2-infected cells. Analysis of a panel of Nsp14 mutants reveals a consistent pattern. Mutants that disable ExoN function remain largely active, whereas N7-MTase mutations impair both pro-inflammatory pathway activation and IFN receptor downregulation. Innate immune modulating functions also require the presence of both the ExoN and N7-MTase domains, likely reflecting that the ExoN domain must be present to enable N7-MTase activity. We further identify multi-functional host protein Tollip as an Nsp14 interactor. Interaction requires the phosphoinositide-binding C2 domain of Tollip and sequences C-terminal to the C2 domain. Full-length Tollip or regions encompassing the Nsp14 interaction domain are sufficient to counteract both Nsp14-mediated and Nsp14-independent activation of NF-κB. Knockdown of Tollip partially reverses IFNAR1 and IFNGR1 downregulation in SARS-CoV-2-infected cells, suggesting the relevance of Nsp14-Tollip interaction for Nsp14 innate immune evasion functions. IMPORTANCE Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) non-struc tural protein 14 (Nsp14) both activates NF-κB, which promotes virus replication and inflammation, and downregulates interferon alpha/beta receptor 1 (IFNAR1), which can render infected cells resistant to the antiviral effects of IFN-α/β. Our study demonstrates that Nsp14 also activates MAPK signaling and downregulates IFN-γ receptor 1 (IFNGR1), causing broader impacts than previously recognized. Data from a panel of Nsp14 mutants suggest that a common underlying effect of Nsp14 may be responsible for its multiple innate immune activities. We further describe a novel interaction between Nsp14 and Tollip, a selective autophagy receptor. We show that Tollip expression downregulates Nsp14 activation of NF-κB and that Tollip knockdown reverses IFNAR1 and IFNGR1 downregulation in SARS-CoV-2 infection, suggesting that Tollip functions as a regulator of Nsp14 innate immune modulation.
AUTHOR CONTRIBUTIONS Naveen Thakur, Conceptualization, Investigation, Methodology, Writing -original draft, Writing -review and editing | Poushali Chakraborty, Formal analysis, Investigation | JoAnn M. Tufariello, Formal analysis, Methodology, Supervision, Writing -original draft, Writing -review and editing | Christopher F. Basler, Conceptualization, Formal analysis, ADDITIONAL FILES The following material is available online. Supplemental Material Supplemental material (mBio01071-25-s0001.pdf). Fig. S1-S5 ; Tables S1-S3 .
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DOI record: { "DOI": "10.1128/mbio.01071-25", "ISSN": [ "2150-7511" ], "URL": "http://dx.doi.org/10.1128/mbio.01071-25", "abstract": "<jats:title>ABSTRACT</jats:title>\n <jats:sec>\n <jats:title/>\n <jats:p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) non-structural protein 14 (Nsp14) possesses an N-terminal exonuclease (ExoN) domain that provides a proofreading function for the viral RNA-dependent RNA polymerase and a C-terminal N7-methyltransferase (N7-MTase) domain that methylates viral mRNA caps. Nsp14 also modulates host functions. This includes the activation of NF-κB and downregulation of interferon alpha/beta receptor 1 (IFNAR1). Here, we demonstrate that Nsp14 exerts broader effects, activating not only NF-κB responses but also extracellular-signal-regulated kinase (ERK), p38, and Jun amino-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) signaling, promoting cytokine production. Furthermore, Nsp14 downregulates not only IFNAR1 but also IFN-γ receptor 1 (IFNGR1), impairing cellular responses to both IFNα and IFNγ. IFNAR1 and IFNGR1 downregulation is via a lysosomal pathway and occurs in SARS-CoV-2-infected cells. Analysis of a panel of Nsp14 mutants reveals a consistent pattern. Mutants that disable ExoN function remain largely active, whereas N7-MTase mutations impair both pro-inflammatory pathway activation and IFN receptor downregulation. Innate immune modulating functions also require the presence of both the ExoN and N7-MTase domains, likely reflecting that the ExoN domain must be present to enable N7-MTase activity. We further identify multi-functional host protein Tollip as an Nsp14 interactor. Interaction requires the phosphoinositide-binding C2 domain of Tollip and sequences C-terminal to the C2 domain. Full-length Tollip or regions encompassing the Nsp14 interaction domain are sufficient to counteract both Nsp14-mediated and Nsp14-independent activation of NF-κB. Knockdown of Tollip partially reverses IFNAR1 and IFNGR1 downregulation in SARS-CoV-2-infected cells, suggesting the relevance of Nsp14-Tollip interaction for Nsp14 innate immune evasion functions.</jats:p>\n <jats:sec>\n <jats:title>IMPORTANCE</jats:title>\n <jats:p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) non-structural protein 14 (Nsp14) both activates NF-κB, which promotes virus replication and inflammation, and downregulates interferon alpha/beta receptor 1 (IFNAR1), which can render infected cells resistant to the antiviral effects of IFN-α/β. Our study demonstrates that Nsp14 also activates MAPK signaling and downregulates IFN-γ receptor 1 (IFNGR1), causing broader impacts than previously recognized. Data from a panel of Nsp14 mutants suggest that a common underlying effect of Nsp14 may be responsible for its multiple innate immune activities. We further describe a novel interaction between Nsp14 and Tollip, a selective autophagy receptor. We show that Tollip expression downregulates Nsp14 activation of NF-κB and that Tollip knockdown reverses IFNAR1 and IFNGR1 downregulation in SARS-CoV-2 infection, suggesting that Tollip functions as a regulator of Nsp14 innate immune modulation.</jats:p>\n </jats:sec>\n </jats:sec>", "alternative-id": [ "10.1128/mbio.01071-25" ], "article-number": "e01071-25", "assertion": [ { "group": { "label": "Publication History", "name": "publication_history" }, "label": "Received", "name": "received", "order": 0, "value": "2025-04-15" }, { "group": { "label": "Publication History", "name": "publication_history" }, "label": "Accepted", "name": "accepted", "order": 2, "value": "2025-05-29" }, { "group": { "label": "Publication History", "name": "publication_history" }, "label": "Published", "name": "published", "order": 3, "value": "2025-06-25" } ], "author": [ { "affiliation": [ { "id": [ { "asserted-by": "publisher", "id": "https://ror.org/04a9tmd77", "id-type": "ROR" } ], "name": "Department of Microbiology, Icahn School of Medicine at Mount Sinai", "place": [ "New York, USA" ] } ], "family": "Thakur", "given": "Naveen", "sequence": "first" }, { "affiliation": [ { "id": [ { "asserted-by": "publisher", "id": "https://ror.org/04a9tmd77", "id-type": "ROR" } ], "name": "Department of Microbiology, Icahn School of Medicine at Mount Sinai", "place": [ "New York, USA" ] } ], "family": "Chakraborty", "given": "Poushali", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0002-2785-1572", "affiliation": [ { "id": [ { "asserted-by": "publisher", "id": "https://ror.org/04a9tmd77", "id-type": "ROR" } ], "name": "Department of Microbiology, Icahn School of Medicine at Mount Sinai", "place": [ "New York, USA" ] } ], "authenticated-orcid": false, "family": "Tufariello", "given": "JoAnn M.", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0003-4195-425X", "affiliation": [ { "id": [ { "asserted-by": "publisher", "id": "https://ror.org/04a9tmd77", "id-type": "ROR" } ], "name": "Department of Microbiology, Icahn School of Medicine at Mount Sinai", "place": [ "New York, USA" ] } ], "authenticated-orcid": true, "family": "Basler", "given": "Christopher F.", "sequence": "additional" } ], "container-title": "mBio", "container-title-short": "mBio", "content-domain": { "crossmark-restriction": true, "domain": [ "journals.asm.org" ] }, "created": { "date-parts": [ [ 2025, 6, 25 ] ], "date-time": "2025-06-25T09:02:51Z", "timestamp": 1750842171000 }, "deposited": { "date-parts": [ [ 2025, 8, 13 ] ], "date-time": "2025-08-13T13:04:49Z", "timestamp": 1755090289000 }, "editor": [ { "affiliation": [], "family": "Lednicky", "given": "John A.", "sequence": "additional" } ], "funder": [ { "DOI": "10.13039/100000060", "award": [ "AI161104" ], "doi-asserted-by": "publisher", "id": [ { "asserted-by": "publisher", "id": "10.13039/100000060", "id-type": "DOI" } ], "name": "National Institute of Allergy and Infectious Diseases" }, { "DOI": "10.13039/100000060", "award": [ "AI164080" ], "doi-asserted-by": "publisher", "id": [ { "asserted-by": "publisher", "id": "10.13039/100000060", "id-type": "DOI" } ], "name": "National Institute of Allergy and Infectious Diseases" } ], "indexed": { "date-parts": [ [ 2025, 8, 15 ] ], "date-time": "2025-08-15T02:39:24Z", "timestamp": 1755225564127, "version": "3.43.0" }, "is-referenced-by-count": 0, "issue": "8", "issued": { "date-parts": [ [ 2025, 8, 13 ] ] }, "journal-issue": { "issue": "8", "published-print": { "date-parts": [ [ 2025, 8, 13 ] ] } }, "language": "en", "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0/", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2025, 8, 13 ] ], "date-time": "2025-08-13T00:00:00Z", "timestamp": 1755043200000 } }, { "URL": "https://journals.asm.org/non-commercial-tdm-license", "content-version": "tdm", "delay-in-days": 0, "start": { "date-parts": [ [ 2025, 8, 13 ] ], "date-time": "2025-08-13T00:00:00Z", "timestamp": 1755043200000 } } ], "link": [ { "URL": "https://journals.asm.org/doi/pdf/10.1128/mbio.01071-25", "content-type": "application/pdf", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://journals.asm.org/doi/pdf/10.1128/mbio.01071-25", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "235", "original-title": [], "prefix": "10.1128", "published": { "date-parts": [ [ 2025, 8, 13 ] ] }, "published-print": { "date-parts": [ [ 2025, 8, 13 ] ] }, "publisher": "American Society for Microbiology", "reference": [ { "key": "e_1_3_5_2_2", "unstructured": "World Health Organization. 2024. 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