{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T04:11:32Z","timestamp":1787803892540,"version":"build-2784847793"},"reference-count":50,"publisher":"National Academy of Sciences","issue":"49","license":[{"start":{"date-parts":[[2024,11,26]],"date-time":"2024-11-26T00:00:00Z","timestamp":1732579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,12,3]]},"abstract":"<jats:p>Phenazine biosynthesis-like domain-containing protein (PBLD) has been reported to be involved in the development of many cancers. However, whether PBLD regulates innate immune responses and viral replication is unclear. In this study, although it was found that the activity of PBLD extends to other PRRs, we focused on the RLR pathway activated via the p53\u2013USP4\u2013MAVS axis in response to virus infections. We found that PBLD deubiquitinates and stabilizes MAVS through ubiquitin-specific protease 4 (USP4) to promote antiviral innate immunity. Mechanistically, PBLD activates the transcription of USP4 via the upregulation of p53. USP4, which is a MAVS-interacting protein, substantially stabilizes the MAVS protein by deconjugating K48-linked ubiquitination chains from the MAVS protein at Lys461 during RNA virus infection. Most intriguingly, RNA virus-infected primary macrophages (peritoneal macrophages, PMs, and bone marrow\u2013derived macrophages, BMDMs) and internal organ cells (lung and liver) from PBLD-deficient mice suppress the IFN-I response and promote viral replication. Notably, PBLD-deficient mice are more susceptible to RNA virus infection than their wild-type littermates. Our findings highlight a unique function of PBLD in antiviral innate immunity through the p53\u2013USP4\u2013MAVS signaling, providing a preliminary basis for research on PBLD as a target molecule for treating RNA virus infection.<\/jats:p>","DOI":"10.1073\/pnas.2401174121","type":"journal-article","created":{"date-parts":[[2024,11,26]],"date-time":"2024-11-26T12:21:54Z","timestamp":1732623714000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":17,"title":["PBLD enhances antiviral innate immunity by promoting the p53\u2013USP4\u2013MAVS signaling axis"],"prefix":"10.1073","volume":"121","author":[{"given":"Fengyun","family":"Chu","sequence":"first","affiliation":[{"name":"Ruminant Diseases Research Center, Key Laboratory of Animal Resistant Biology of Shandong, College of Life Sciences, Shandong Normal University, Jinan 250358, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peili","family":"Hou","sequence":"additional","affiliation":[{"name":"Ruminant Diseases Research Center, Key Laboratory of Animal Resistant Biology of Shandong, College of Life Sciences, Shandong Normal University, Jinan 250358, People\u2019s Republic of China"},{"name":"Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Shandong Agricultural University, Taian 271018, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1629-1172","authenticated-orcid":false,"given":"Hongchao","family":"Zhu","sequence":"additional","affiliation":[{"name":"Ruminant Diseases Research Center, Key Laboratory of Animal Resistant Biology of Shandong, College of Life Sciences, Shandong Normal University, Jinan 250358, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Gao","sequence":"additional","affiliation":[{"name":"Ruminant Diseases Research Center, Key Laboratory of Animal Resistant Biology of Shandong, College of Life Sciences, Shandong Normal University, Jinan 250358, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Ruminant Diseases Research Center, Key Laboratory of Animal Resistant Biology of Shandong, College of Life Sciences, Shandong Normal University, Jinan 250358, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3254-1242","authenticated-orcid":false,"given":"Wenqi","family":"He","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun 130062, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Ren","sequence":"additional","affiliation":[{"name":"Ruminant Diseases Research Center, Key Laboratory of Animal Resistant Biology of Shandong, College of Life Sciences, Shandong Normal University, Jinan 250358, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Li","sequence":"additional","affiliation":[{"name":"Ruminant Diseases Research Center, Key Laboratory of Animal Resistant Biology of Shandong, College of Life Sciences, Shandong Normal University, Jinan 250358, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Liu","sequence":"additional","affiliation":[{"name":"Ruminant Diseases Research Center, Key Laboratory of Animal Resistant Biology of Shandong, College of Life Sciences, Shandong Normal University, Jinan 250358, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Chang He","sequence":"additional","affiliation":[{"name":"The College of Arts and Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongmei","family":"Wang","sequence":"additional","affiliation":[{"name":"Ruminant Diseases Research Center, Key Laboratory of Animal Resistant Biology of Shandong, College of Life Sciences, Shandong Normal University, Jinan 250358, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuwei","family":"Gao","sequence":"additional","affiliation":[{"name":"Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun 130122, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongbin","family":"He","sequence":"additional","affiliation":[{"name":"Ruminant Diseases Research Center, Key Laboratory of Animal Resistant Biology of Shandong, College of Life Sciences, Shandong Normal University, Jinan 250358, People\u2019s Republic of China"},{"name":"Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Shandong Agricultural University, Taian 271018, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,11,26]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellin.2023.100079"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109197"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-020-00602-7"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2021.01.002"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01080-07"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04734"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.06.041"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.03.029"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.08.012"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04193"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2100983"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-11258-x"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1842"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02351-20"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-018-0107-6"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-019-0926-z"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v19.i18.2781"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-022-02197-x"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.6358"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-021-03843-0"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01017-21"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13567-022-01043-y"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.19.4.2465"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2023.104660"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00030-13"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgs145"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1039\/D0SC04670A"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a026047"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M512074200"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1111\/jfd.12622"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms222413397"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-021-00807-4"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2014.03.040"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2016.125"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2023.05.018"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00031-13"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2011.11"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20111358"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.328187"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-018-0120-9"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2012.12.016"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1002\/tox.23617"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.3390\/v2010298"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.79.14.8802-8811.2005"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2019.02.005"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vetmic.2019.108494"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-023-01103-z"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13052-018-0569-7"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-33909-2"},{"key":"e_1_3_4_50_2","unstructured":"F. Y. Chu Data from \u201cPBLD enhances antiviral innate immunity by promoting the p53-USP4-MAVS signaling axis.\u201d Figshare. http:\/\/doi.org\/10.6084\/m9.figshare.27637155.v1. Deposited 8 November 2024."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2401174121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,26]],"date-time":"2024-11-26T12:23:23Z","timestamp":1732623803000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2401174121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,26]]},"references-count":50,"journal-issue":{"issue":"49","published-print":{"date-parts":[[2024,12,3]]}},"alternative-id":["10.1073\/pnas.2401174121"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2401174121","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,26]]},"assertion":[{"value":"2024-01-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-08-22","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2401174121"}}