{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T03:03:33Z","timestamp":1787022213923,"version":"build-2736575974"},"update-to":[{"DOI":"10.1371\/journal.ppat.1013683","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T00:00:00Z","timestamp":1763078400000}}],"reference-count":36,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T00:00:00Z","timestamp":1762473600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32400140"],"award-info":[{"award-number":["32400140"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005273","name":"Natural Science Foundation of Yunnan Province","doi-asserted-by":"publisher","award":["202401AW070017"],"award-info":[{"award-number":["202401AW070017"]}],"id":[{"id":"10.13039\/501100005273","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>HIV-1 replication, transcription and latency are correlated with the activation of NF-\u03baB signaling. C-terminus of Hsc70-interacting protein (CHIP or STUB1), a cellular E3 ligase, has been reported to inhibit Tat-mediated HIV-1 LTR promoter activity by degrading Tat. In this study, we demonstrated that CHIP modulates HIV infection by limiting viral transcription through an uncharacterized mechanism involving the negative regulation of TRAF6-NF-\u03baB signaling. Mechanistically, CHIP targets the NF-\u03baB signaling transducer TRAF6 but not TRAF2 or p65 for degradation via the ubiquitin\u2013proteasome pathway, leading to the inhibition of TRAF6-mediated NF-\u03baB signaling, which in turn suppresses NF-\u03baB-dependent HIV-1 LTR transcription. Notably, in addition to the U-box domain, which is well known for protein degradation, the TPR domain of CHIP plays an independent role in facilitating the proteasome-mediated degradation of TRAF6 via K48-linked polyubiquitination. Furthermore, CHIP plays an inhibitory role in the reactivation of HIV-1 latency in various models, in concert with its repressive effect on the NF-\u03baB pathway. Thus, these findings reveal that CHIP is a novel repressor of NF-\u03baB-driven HIV-1 promoter transactivation, providing new insights into the molecular mechanisms by which upstream NF-\u03baB signaling influences HIV-1 replication, transcription and latency.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013683","type":"journal-article","created":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T18:46:36Z","timestamp":1762541196000},"page":"e1013683","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["CHIP\/STUB1 suppresses the transcription and latent reactivation of HIV-1 via the TRAF6-NF-\u03baB-HIV-LTR axis"],"prefix":"10.1371","volume":"21","author":[{"given":"Wei-Hua","family":"Zheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sen-Ying","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ze-Lan","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Run-Ze","family":"Ni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8380-932X","authenticated-orcid":true,"given":"Dan","family":"Mu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,11,7]]},"reference":[{"key":"ppat.1013683.ref001","doi-asserted-by":"crossref","first-page":"45","DOI":"10.5772\/61948","article-title":"Molecular mechanisms controlling HIV transcription and latency \u2013 implications for therapeutic viral reactivation.","volume-title":"Adv Mol Retrovirol","author":"MD R\u00f6lling","year":"2016"},{"issue":"5","key":"ppat.1013683.ref002","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1016\/j.immuni.2018.04.030","article-title":"Targeting the Latent Reservoir for HIV-1","volume":"48","author":"S Sengupta","year":"2018","journal-title":"Immunity"},{"issue":"1","key":"ppat.1013683.ref003","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1146\/annurev-virology-101416-041646","article-title":"The molecular basis for human immunodeficiency virus latency","volume":"4","author":"U Mbonye","year":"2017","journal-title":"Annu Rev Virol"},{"issue":"4","key":"ppat.1013683.ref004","doi-asserted-by":"crossref","first-page":"286","DOI":"10.2174\/157016208785132563","article-title":"Factors controlling chromatin organization and nucleosome positioning for establishment and maintenance of HIV latency","volume":"6","author":"I Sadowski","year":"2008","journal-title":"Curr HIV Res"},{"issue":"1","key":"ppat.1013683.ref005","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1097\/COH.0b013e32834124fd","article-title":"NF-\u03baB\/Rel: agonist and antagonist roles in HIV-1 latency","volume":"6","author":"JKL Chan","year":"2011","journal-title":"Curr Opin HIV AIDS"},{"issue":"1","key":"ppat.1013683.ref006","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/1750-2187-8-7","article-title":"TRAF molecules in cell signaling and in human diseases","volume":"8","author":"P Xie","year":"2013","journal-title":"J Mol Signal"},{"issue":"4","key":"ppat.1013683.ref007","doi-asserted-by":"crossref","first-page":"1613","DOI":"10.1093\/nar\/gkv1151","article-title":"HSP70 binding protein 1 (HspBP1) suppresses HIV-1 replication by inhibiting NF-\u03baB mediated activation of viral gene expression","volume":"44","author":"P Chaudhary","year":"2016","journal-title":"Nucleic Acids Res"},{"issue":"17","key":"ppat.1013683.ref008","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.01057-20","article-title":"NF-\u03baB-interacting long noncoding RNA regulates HIV-1 replication and latency by repressing NF-\u03baB signaling","volume":"94","author":"H Wang","year":"2020","journal-title":"J Virol"},{"issue":"13","key":"ppat.1013683.ref009","doi-asserted-by":"crossref","first-page":"7528","DOI":"10.1128\/JVI.00239-14","article-title":"Tumor suppressor cylindromatosis (CYLD) controls HIV transcription in an NF-\u03baB-dependent manner","volume":"88","author":"L Manganaro","year":"2014","journal-title":"J Virol"},{"issue":"1","key":"ppat.1013683.ref010","doi-asserted-by":"crossref","first-page":"3343","DOI":"10.1038\/s41467-023-39056-6","article-title":"TRIM5\u03b1 recruits HDAC1 to p50 and Sp1 and promotes H3K9 deacetylation at the HIV-1 LTR","volume":"14","author":"X-H Ran","year":"2023","journal-title":"Nat Commun"},{"issue":"11","key":"ppat.1013683.ref011","doi-asserted-by":"crossref","DOI":"10.15252\/embr.201949305","article-title":"PEBP1 suppresses HIV transcription and induces latency by inactivating MAPK\/NF-\u03baB signaling","volume":"21","author":"X Yang","year":"2020","journal-title":"EMBO Rep"},{"issue":"3","key":"ppat.1013683.ref012","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.chom.2015.08.009","article-title":"BIRC2\/cIAP1 is a negative regulator of HIV-1 transcription and can be targeted by smac mimetics to promote reversal of viral latency","volume":"18","author":"L Pache","year":"2015","journal-title":"Cell Host Microbe"},{"issue":"7083","key":"ppat.1013683.ref013","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1038\/nature04600","article-title":"CHIP-mediated stress recovery by sequential ubiquitination of substrates and Hsp70","volume":"440","author":"S-B Qian","year":"2006","journal-title":"Nature"},{"issue":"9","key":"ppat.1013683.ref014","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1080\/10985549.2023.2239694","article-title":"Degradation of CDK9 by ubiquitin E3 ligase STUB1 regulates P-TEFb level and its functions for global target gene expression within mammalian cells","volume":"43","author":"S Basu","year":"2023","journal-title":"Mol Cell Biol"},{"issue":"2","key":"ppat.1013683.ref015","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.immuni.2013.08.006","article-title":"The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3","volume":"39","author":"Z Chen","year":"2013","journal-title":"Immunity"},{"issue":"22","key":"ppat.1013683.ref016","doi-asserted-by":"crossref","first-page":"4461","DOI":"10.1128\/MCB.00480-13","article-title":"The ubiquitin ligase CHIP prevents SirT6 degradation through noncanonical ubiquitination","volume":"33","author":"SM Ronnebaum","year":"2013","journal-title":"Mol Cell Biol"},{"issue":"1","key":"ppat.1013683.ref017","article-title":"Stability of the cancer target DDIAS is regulated by the CHIP\/HSP70 pathway in lung cancer cells","volume":"8","author":"K-J Won","year":"2017","journal-title":"Cell Death Dis"},{"issue":"20","key":"ppat.1013683.ref018","doi-asserted-by":"crossref","first-page":"12847","DOI":"10.1073\/pnas.202365899","article-title":"Chaperone-dependent E3 ubiquitin ligase CHIP mediates a degradative pathway for c-ErbB2\/Neu","volume":"99","author":"W Xu","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"6","key":"ppat.1013683.ref019","doi-asserted-by":"crossref","first-page":"4869","DOI":"10.1074\/jbc.M305838200","article-title":"CHIP-Hsc70 complex ubiquitinates phosphorylated tau and enhances cell survival","volume":"279","author":"H Shimura","year":"2004","journal-title":"J Biol Chem"},{"issue":"1","key":"ppat.1013683.ref020","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1038\/s41467-018-03563-8","article-title":"MLL5 suppresses antiviral innate immune response by facilitating STUB1-mediated RIG-I degradation","volume":"9","author":"P Zhou","year":"2018","journal-title":"Nat Commun"},{"issue":"6","key":"ppat.1013683.ref021","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1016\/j.gendis.2021.08.003","article-title":"Chaperone-assisted E3 ligase CHIP: a double agent in cancer","volume":"9","author":"S Kumar","year":"2021","journal-title":"Genes Dis"},{"issue":"18","key":"ppat.1013683.ref022","doi-asserted-by":"crossref","first-page":"7283","DOI":"10.1074\/jbc.RA118.007257","article-title":"The host cell ubiquitin ligase protein CHIP is a potent suppressor of HIV-1 replication","volume":"294","author":"A Ali","year":"2019","journal-title":"J Biol Chem"},{"issue":"8","key":"ppat.1013683.ref023","doi-asserted-by":"crossref","first-page":"1868","DOI":"10.1093\/emboj\/cdg188","article-title":"HIV reproducibly establishes a latent infection after acute infection of T cells in vitro","volume":"22","author":"A Jordan","year":"2003","journal-title":"EMBO J"},{"issue":"5","key":"ppat.1013683.ref024","doi-asserted-by":"crossref","first-page":"495","DOI":"10.3390\/v12050495","article-title":"Cellular factors targeting HIV-1 transcription and viral RNA transcripts","volume":"12","author":"R Nchioua","year":"2020","journal-title":"Viruses"},{"issue":"12","key":"ppat.1013683.ref025","doi-asserted-by":"crossref","first-page":"3612","DOI":"10.1002\/jcb.23292","article-title":"Ubiquitin ligase CHIP induces TRAF2 proteasomal degradation and NF-\u03baB inactivation to regulate breast cancer cell invasion","volume":"112","author":"KW Jang","year":"2011","journal-title":"J Cell Biochem"},{"issue":"5","key":"ppat.1013683.ref026","doi-asserted-by":"crossref","first-page":"2096","DOI":"10.3892\/ijo.2015.2893","article-title":"The ubiquitin ligase CHIP inactivates NF-\u03baB signaling and impairs the ability of migration and invasion in gastric cancer cells","volume":"46","author":"F Liu","year":"2015","journal-title":"Int J Oncol"},{"key":"ppat.1013683.ref027","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41413-018-0010-2","article-title":"CHIP regulates bone mass by targeting multiple TRAF family members in bone marrow stromal cells","volume":"6","author":"T Wang","year":"2018","journal-title":"Bone Res"},{"issue":"6599","key":"ppat.1013683.ref028","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1038\/383443a0","article-title":"TRAF6 is a signal transducer for interleukin-1","volume":"383","author":"Z Cao","year":"1996","journal-title":"Nature"},{"issue":"7073","key":"ppat.1013683.ref029","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/nature04369","article-title":"Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6","volume":"439","author":"H H\u00e4cker","year":"2006","journal-title":"Nature"},{"issue":"18","key":"ppat.1013683.ref030","doi-asserted-by":"crossref","first-page":"11704","DOI":"10.1074\/jbc.M114.635086","article-title":"Carboxyl terminus of HSC70-interacting protein (CHIP) down-regulates NF-\u03baB-inducing kinase (NIK) and suppresses NIK-induced liver injury","volume":"290","author":"B Jiang","year":"2015","journal-title":"J Biol Chem"},{"issue":"7","key":"ppat.1013683.ref031","doi-asserted-by":"crossref","first-page":"1854","DOI":"10.1002\/art.38521","article-title":"Carboxyl terminus of Hsp70-interacting protein regulation of osteoclast formation in mice through promotion of tumor necrosis factor receptor-associated factor 6 protein degradation","volume":"66","author":"S Li","year":"2014","journal-title":"Arthritis Rheumatol"},{"issue":"5","key":"ppat.1013683.ref032","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1093\/carcin\/bgt393","article-title":"CHIP\/Stub1 functions as a tumor suppressor and represses NF-\u03baB-mediated signaling in colorectal cancer","volume":"35","author":"Y Wang","year":"2014","journal-title":"Carcinogenesis"},{"issue":"10","key":"ppat.1013683.ref033","doi-asserted-by":"crossref","first-page":"2099","DOI":"10.1084\/jem.20102667","article-title":"E3 ubiquitin ligase CHIP facilitates Toll-like receptor signaling by recruiting and polyubiquitinating Src and atypical PKC{zeta}","volume":"208","author":"M Yang","year":"2011","journal-title":"J Exp Med"},{"issue":"1","key":"ppat.1013683.ref034","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1038\/s41420-021-00637-3","article-title":"CHIP promotes the activation of NF-\u03baB signaling through enhancing the K63-linked ubiquitination of TAK1","volume":"7","author":"Y Liu","year":"2021","journal-title":"Cell Death Discov"},{"issue":"5","key":"ppat.1013683.ref035","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1016\/j.jmb.2011.04.005","article-title":"Reciprocal regulation of human immunodeficiency virus-1 gene expression and replication by heat shock proteins 40 and 70","volume":"410","author":"M Kumar","year":"2011","journal-title":"J Mol Biol"},{"issue":"3","key":"ppat.1013683.ref036","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.str.2015.01.003","article-title":"A bipartite interaction between Hsp70 and CHIP regulates ubiquitination of chaperoned client proteins","volume":"23","author":"H Zhang","year":"2015","journal-title":"Structure"}],"updated-by":[{"DOI":"10.1371\/journal.ppat.1013683","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T00:00:00Z","timestamp":1763078400000}}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1013683","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T18:51:56Z","timestamp":1763146316000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1013683"}},"subtitle":[],"editor":[{"given":"Susan R.","family":"Ross","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,11,7]]},"references-count":36,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11,7]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1013683","relation":{},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,7]]}}}