{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:00:35Z","timestamp":1791230435520,"version":"4.1.0"},"reference-count":79,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T00:00:00Z","timestamp":1755043200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T00:00:00Z","timestamp":1755043200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI161104"],"award-info":[{"award-number":["AI161104"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI164080"],"award-info":[{"award-number":["AI164080"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2025,8,13]]},"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-\u03baB and downregulation of interferon alpha\/beta receptor 1 (IFNAR1). Here, we demonstrate that Nsp14 exerts broader effects, activating not only NF-\u03baB 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-\u03b3 receptor 1 (IFNGR1), impairing cellular responses to both IFN\u03b1 and IFN\u03b3. 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-\u03baB. 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-\u03baB, 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-\u03b1\/\u03b2. Our study demonstrates that Nsp14 also activates MAPK signaling and downregulates IFN-\u03b3 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-\u03baB 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>","DOI":"10.1128\/mbio.01071-25","type":"journal-article","created":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T09:02:51Z","timestamp":1750842171000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":3,"title":["SARS-CoV-2 Nsp14 binds Tollip and activates pro-inflammatory pathways while downregulating interferon-\u03b1 and interferon-\u03b3 receptors"],"prefix":"10.1128","volume":"16","author":[{"given":"Naveen","family":"Thakur","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04a9tmd77","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology, Icahn School of Medicine at Mount Sinai","place":["New York, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Poushali","family":"Chakraborty","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04a9tmd77","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology, Icahn School of Medicine at Mount Sinai","place":["New York, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2785-1572","authenticated-orcid":false,"given":"JoAnn M.","family":"Tufariello","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04a9tmd77","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology, Icahn School of Medicine at Mount Sinai","place":["New York, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4195-425X","authenticated-orcid":true,"given":"Christopher F.","family":"Basler","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04a9tmd77","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology, Icahn School of Medicine at Mount Sinai","place":["New York, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","unstructured":"World Health Organization. 2024. WHO COVID-19 dashboard. Available from: https:\/\/data.who.int\/dashboards\/covid19\/deaths. 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