{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T02:27:16Z","timestamp":1790389636058,"version":"4.1.0"},"reference-count":34,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2018,1,1]],"date-time":"2018-01-01T00:00:00Z","timestamp":1514764800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"Harbin Veterinary Research Institute","award":["SKLVBP2017012"],"award-info":[{"award-number":["SKLVBP2017012"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31502089"],"award-info":[{"award-number":["31502089"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005046","name":"Natural Science Foundation of Heilongjiang Province","doi-asserted-by":"publisher","award":["QC2017028"],"award-info":[{"award-number":["QC2017028"]}],"id":[{"id":"10.13039\/501100005046","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004573","name":"Ministry of Agriculture of the People's Republic of China","doi-asserted-by":"publisher","award":["948 plan 2014-Z10"],"award-info":[{"award-number":["948 plan 2014-Z10"]}],"id":[{"id":"10.13039\/501100004573","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007709","name":"Michigan State University","doi-asserted-by":"publisher","award":["Bertina Wentworth endowed fellowship"],"award-info":[{"award-number":["Bertina Wentworth endowed fellowship"]}],"id":[{"id":"10.13039\/100007709","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007709","name":"Michigan State University","doi-asserted-by":"publisher","award":["Russell B. Duvall endowed fellowship"],"award-info":[{"award-number":["Russell B. Duvall endowed fellowship"]}],"id":[{"id":"10.13039\/100007709","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2018,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>Innate immunity provides an immediate defense against infection after host cells sense danger signals from microbes. Endoplasmic reticulum (ER) stress arises from accumulation of misfolded\/unfolded proteins when protein load overwhelms the ER folding capacity, which activates the unfolded protein response (UPR) to restore ER homeostasis. Here, we show that a mechanism for antiviral innate immunity is triggered after the ER stress pathway senses viral glycoproteins. When hemagglutinin (HA) glycoproteins from influenza A virus (IAV) are expressed in cells, ER stress is induced, resulting in rapid HA degradation via proteasomes. The ER-associated protein degradation (ERAD) pathway, an important UPR function for destruction of aberrant proteins, mediates HA degradation. Three class I \u03b1-mannosidases were identified to play a critical role in the degradation process, including EDEM1, EDEM2, and ERManI. HA degradation requires either ERManI enzymatic activity or EDEM1\/EDEM2 enzymatic activity when ERManI is not expressed, indicating that demannosylation is a critical step for HA degradation. Silencing of EDEM1, EDEM2, and ERManI strongly increases HA expression and promotes IAV replication. Thus, the ER stress pathway senses influenza HA as \u201cnonself\u201d or misfolded protein and sorts HA to ERAD for degradation, resulting in inhibition of IAV replication.<\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            Viral nucleic acids are recognized as important inducers of innate antiviral immune responses that are sensed by multiple classes of sensors, but other inducers and sensors of viral innate immunity need to be identified and characterized. Here, we used IAV to investigate how host innate immunity is activated. We found that IAV HA glycoproteins induce ER stress, resulting in HA degradation via ERAD and consequent inhibition of IAV replication. In addition, we have identified three class I \u03b1-mannosidases, EDEM1, EDEM2, and ERManI, which play a critical role in initiating HA degradation. Knockdown of these proteins substantially increases HA expression and IAV replication. The enzymatic activities and joint actions of these mannosidases are required for this antiviral activity. Our results suggest that viral glycoproteins induce a strong innate antiviral response through activating the ER stress pathway during viral infection.\n          <\/jats:p>","DOI":"10.1128\/jvi.01690-17","type":"journal-article","created":{"date-parts":[[2017,10,19]],"date-time":"2017-10-19T00:25:30Z","timestamp":1508372730000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":46,"title":["Innate Sensing of Influenza A Virus Hemagglutinin Glycoproteins by the Host Endoplasmic Reticulum (ER) Stress Pathway Triggers a Potent Antiviral Response via ER-Associated Protein Degradation"],"prefix":"10.1128","volume":"92","author":[{"given":"Dylan A.","family":"Frabutt","sequence":"first","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Wang","sequence":"additional","affiliation":[{"name":"Harbin Veterinary Research Institute, CAAS-Michigan State University Joint Laboratory of Innate Immunity, State Key Laboratory of Veterinary Biotechnology, Chinese Academy of Agricultural Sciences, Harbin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sana","family":"Riaz","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard C.","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1098-7385","authenticated-orcid":false,"given":"Yong-Hui","family":"Zheng","sequence":"additional","affiliation":[{"name":"Harbin Veterinary Research Institute, CAAS-Michigan State University Joint Laboratory of Innate Immunity, State Key Laboratory of Veterinary Biotechnology, Chinese Academy of Agricultural Sciences, Harbin, China"},{"name":"Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3123"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2016.01.010"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2014.00518"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3800"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2546"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(06)15003-X"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2012.07.005"},{"key":"e_1_3_2_9_2","volume-title":"Fields virology","author":"Knipe DM","year":"2013","unstructured":"Knipe DM, Howley PM, Cohen JI, Griffin DE, Lamb RA, Martin MA, Racaniello VR, Roizman B (ed). 2013. Fields virology, 6th ed. Lippincott Williams & Wilkins Health, Philadelphia, PA.","edition":"6"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R110.129809"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.3390\/v6031294"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00779-06"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.284695"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.05.012"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a013169"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R700048200"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.3.913"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1996.tb00659.x"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.139.3.613"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.768168"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M806897200"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00879-06"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1430537100"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M809607200"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.675207"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.552091"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2007.04.070"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.100133697"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.013474"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2014.00222"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2014.00330"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.3390\/v8090255"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00801-14"},{"key":"e_1_3_2_34_2","first-page":"14G","article-title":"The specificity of the yeast and human class I ER alpha 1,2-mannosidases involved in ER quality control is not as strict previously reported","volume":"12","author":"Herscovics A","year":"2002","unstructured":"Herscovics A, Romero PA, Tremblay LO. 2002. The specificity of the yeast and human class I ER alpha 1,2-mannosidases involved in ER quality control is not as strict previously reported. Glycobiology 12:14G\u201315G.","journal-title":"Glycobiology"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.259085"}],"container-title":["Journal of Virology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/JVI.01690-17","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/JVI.01690-17","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,5]],"date-time":"2022-03-05T14:31:16Z","timestamp":1646490676000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/JVI.01690-17"}},"subtitle":[],"editor":[{"given":"Stacey","family":"Schultz-Cherry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2018,1]]},"references-count":34,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2018,1]]}},"alternative-id":["10.1128\/JVI.01690-17"],"URL":"https:\/\/doi.org\/10.1128\/jvi.01690-17","relation":{},"ISSN":["0022-538X","1098-5514"],"issn-type":[{"value":"0022-538X","type":"print"},{"value":"1098-5514","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,1]]},"assertion":[{"value":"2017-09-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-10-10","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-12-14","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e01690-17"}}