{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T21:38:23Z","timestamp":1777585103599,"version":"3.51.4"},"reference-count":67,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,9,1]],"date-time":"2020-09-01T00:00:00Z","timestamp":1598918400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["P01 AI09093"],"award-info":[{"award-number":["P01 AI09093"]}],"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":["R01 AI124843"],"award-info":[{"award-number":["R01 AI124843"]}],"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":["P30 AI036214"],"award-info":[{"award-number":["P30 AI036214"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["404687549"],"award-info":[{"award-number":["404687549"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The infectious life cycle of the human immunodeficiency virus type 1 (HIV-1) is characterized by an ongoing battle between a compendium of cellular proteins that either promote or oppose viral replication. On the one hand, HIV-1 utilizes dependency factors to support and sustain infection and complete the viral life cycle. On the other hand, both inducible and constitutively expressed host factors mediate efficient and functionally diverse antiviral processes that counteract an infection. To shed light into the complex interplay between HIV-1 and cellular proteins, we previously performed a targeted siRNA screen to identify and characterize novel regulators of viral replication and identified Cullin 3 (Cul3) as a previously undescribed factor that negatively regulates HIV-1 replication. Cul3 is a component of E3-ubiquitin ligase complexes that target substrates for ubiquitin-dependent proteasomal degradation. In the present study, we show that Cul3 is expressed in HIV-1 target cells, such as CD4+ T cells, monocytes, and macrophages and depletion of Cul3 using siRNA or CRISPR\/Cas9 increases HIV-1 infection in immortalized cells and primary CD4+ T cells. Conversely, overexpression of Cul3 reduces HIV-1 infection in single replication cycle assays. Importantly, the antiviral effect of Cul3 was mapped to the transcriptional stage of the viral life cycle, an effect which is independent of its role in regulating the G1\/S cell cycle transition. Using isogenic viruses that only differ in their promotor region, we find that the NF-\u03baB\/NFAT transcription factor binding sites in the LTR are essential for Cul3-dependent regulation of viral gene expression. Although Cul3 effectively suppresses viral gene expression, HIV-1 does not appear to antagonize the antiviral function of Cul3 by targeting it for degradation. Taken together, these results indicate that Cul3 is a negative regulator of HIV-1 transcription which governs productive viral replication in infected cells.<\/jats:p>","DOI":"10.3390\/cells9092010","type":"journal-article","created":{"date-parts":[[2020,9,1]],"date-time":"2020-09-01T08:53:43Z","timestamp":1598950423000},"page":"2010","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["The E3 Ubiquitin-Protein Ligase Cullin 3 Regulates HIV-1 Transcription"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9660-8058","authenticated-orcid":false,"given":"Simon","family":"Langer","sequence":"first","affiliation":[{"name":"Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA"},{"name":"Boehringer Ingelheim Pharma GmbH &amp; Co. KG, 55216 Ingelheim am Rhein, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2357-6718","authenticated-orcid":false,"given":"Xin","family":"Yin","sequence":"additional","affiliation":[{"name":"Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4174-8950","authenticated-orcid":false,"given":"Arturo","family":"Diaz","sequence":"additional","affiliation":[{"name":"Department of Biology, La Sierra University, Riverside, CA 92515, USA"},{"name":"The Nomis Center for Immunobiology and Microbial Pathogenesis, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alex J.","family":"Portillo","sequence":"additional","affiliation":[{"name":"Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA"},{"name":"Atara Biotherapeutics, Inc., Thousand Oaks, CA 91320, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David E.","family":"Gordon","sequence":"additional","affiliation":[{"name":"Department of Cellular &amp; Molecular Pharmacology, University of California, San Francisco, CA 94143, USA"},{"name":"Gladstone Institutes, San Francisco, CA 94158, USA"},{"name":"Quantitative Biosciences Institute (QBI), San Francisco, CA 94158, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Umu H.","family":"Rogers","sequence":"additional","affiliation":[{"name":"Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA"},{"name":"UC San Diego School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John M.","family":"Marlett","sequence":"additional","affiliation":[{"name":"The Nomis Center for Immunobiology and Microbial Pathogenesis, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nevan J.","family":"Krogan","sequence":"additional","affiliation":[{"name":"Department of Cellular &amp; Molecular Pharmacology, University of California, San Francisco, CA 94143, USA"},{"name":"Gladstone Institutes, San Francisco, CA 94158, USA"},{"name":"Quantitative Biosciences Institute (QBI), San Francisco, CA 94158, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John A. T.","family":"Young","sequence":"additional","affiliation":[{"name":"Roche Pharma Research and Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4193-1042","authenticated-orcid":false,"given":"Lars","family":"Pache","sequence":"additional","affiliation":[{"name":"Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sumit K.","family":"Chanda","sequence":"additional","affiliation":[{"name":"Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1146\/annurev.biochem.67.1.1","article-title":"HIV-1: Fifteen proteins and an RNA","volume":"67","author":"Frankel","year":"1998","journal-title":"Annu. 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