{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T02:12:10Z","timestamp":1791252730285,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1008504","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,1,7]],"date-time":"2021-01-07T00:00:00Z","timestamp":1609977600000}}],"reference-count":63,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2020,12,23]],"date-time":"2020-12-23T00:00:00Z","timestamp":1608681600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/NCI","award":["RO1CA135362"],"award-info":[{"award-number":["RO1CA135362"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia\/lymphoma (ATLL), and the neurological disease HTLV-1-associated myelopathy\/tropical spastic paraparesis (HAM\/TSP). The HTLV-1 Tax protein persistently activates the NF-\u03baB pathway to enhance the proliferation and survival of HTLV-1 infected T cells. Lysine 63 (K63)-linked polyubiquitination of Tax provides an important regulatory mechanism that promotes Tax-mediated interaction with the IKK complex and activation of NF-\u03baB; however, the host proteins regulating Tax ubiquitination are largely unknown. To identify new Tax interacting proteins that may regulate its ubiquitination we conducted a yeast two-hybrid screen using Tax as bait. This screen yielded the E3\/E4 ubiquitin conjugation factor UBE4B as a novel binding partner for Tax. Here, we confirmed the interaction between Tax and UBE4B in mammalian cells by co-immunoprecipitation assays and demonstrated colocalization by proximity ligation assay and confocal microscopy. Overexpression of UBE4B specifically enhanced Tax-induced NF-\u03baB activation, whereas knockdown of UBE4B impaired Tax-induced NF-\u03baB activation and the induction of NF-\u03baB target genes in T cells and ATLL cell lines. Furthermore, depletion of UBE4B with shRNA resulted in apoptotic cell death and diminished the proliferation of ATLL cell lines. Finally, overexpression of UBE4B enhanced Tax polyubiquitination, and knockdown or CRISPR\/Cas9-mediated knockout of UBE4B attenuated both K48- and K63-linked polyubiquitination of Tax. Collectively, these results implicate UBE4B in HTLV-1 Tax polyubiquitination and downstream NF-\u03baB activation.<\/jats:p>","DOI":"10.1371\/journal.ppat.1008504","type":"journal-article","created":{"date-parts":[[2020,12,23]],"date-time":"2020-12-23T14:48:49Z","timestamp":1608734929000},"page":"e1008504","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":22,"title":["The E3\/E4 ubiquitin conjugation factor UBE4B interacts with and ubiquitinates the HTLV-1 Tax oncoprotein to promote NF-\u03baB activation"],"prefix":"10.1371","volume":"16","author":[{"given":"Suchitra","family":"Mohanty","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teng","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2523-1441","authenticated-orcid":true,"given":"Young Bong","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5614-3559","authenticated-orcid":true,"given":"Alfonso","family":"Lavorgna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6129-7341","authenticated-orcid":true,"given":"Jiawen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1197-6765","authenticated-orcid":true,"given":"Edward William","family":"Harhaj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2020,12,23]]},"reference":[{"key":"ppat.1008504.ref001","doi-asserted-by":"crossref","first-page":"388","DOI":"10.3389\/fmicb.2012.00388","article-title":"Epidemiological Aspects and World Distribution 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