{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T15:45:42Z","timestamp":1766159142053,"version":"3.37.3"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2023,4,28]],"date-time":"2023-04-28T00:00:00Z","timestamp":1682640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100015691","name":"HHS | NIH | NIAID | Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI054977"],"award-info":[{"award-number":["R01AI054977"]}],"id":[{"id":"10.13039\/100015691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,6,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Here we report that the murine Tox gene encodes two proteins from a single mRNA, and we investigate the mechanism of production and function of these proteoforms. The annotated thymocyte selection\u2013associated HMG-box protein (TOX) coding sequence is predicted to produce a 526-aa protein (TOXFL). However, Western blots reveal two bands. We found that the lower band consists of an N-terminally truncated variant of TOX (TOX\u0394N), whereas the slower-migrating band is TOXFL. The TOX\u0394N proteoform is alternatively translated via leaky ribosomal scanning from an evolutionarily conserved translation initiation site downstream of the annotated translation initiation site. When expressed exogenously from a cDNA in murine CD8 T cells or HEK cells, or endogenously from the murine Tox locus, both forms are translated, although the ratio of TOXFL\/TOX\u0394N significantly varies with cellular context. This includes regulation of proteoform production during development of murine CD4 T cells in the thymus, where the positive selection of CD4+CD8+ cells and subsequent differentiation to CD4+CD8lo transitional and CD4SP cell subsets is associated with both an increase in total TOX protein and increased TOX\u0394N production relative to TOXFL. Finally, we found that sole expression of TOXFL had a greater effect on gene regulation during chronic stimulation of murine CD8 T cells in culture mimicking exhaustion than did TOX\u0394N, including uniquely regulated cell cycle and other genes.<\/jats:p>","DOI":"10.4049\/jimmunol.2200659","type":"journal-article","created":{"date-parts":[[2023,4,28]],"date-time":"2023-04-28T14:53:01Z","timestamp":1682693581000},"page":"1889-1898","source":"Crossref","is-referenced-by-count":1,"title":["The <i>Tox<\/i> Gene Encodes Two Proteins with Distinct and Shared Roles in Gene Regulation"],"prefix":"10.1093","volume":"210","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7279-0326","authenticated-orcid":false,"given":"Alyson R","family":"Yeckes","sequence":"first","affiliation":[{"name":"Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center , Los Angeles, CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4118-3088","authenticated-orcid":false,"given":"Aaron R","family":"Victor","sequence":"additional","affiliation":[{"name":"Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center , Los Angeles, CA"},{"name":"Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center , Los Angeles, CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3093-4360","authenticated-orcid":false,"given":"Zheng","family":"Zhu","sequence":"additional","affiliation":[{"name":"Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center , Los Angeles, CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meena","family":"Narayanan","sequence":"additional","affiliation":[{"name":"Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center , Los Angeles, CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bharani","family":"Srinivasan","sequence":"additional","affiliation":[{"name":"Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center , Los Angeles, CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bethany","family":"Bruce","sequence":"additional","affiliation":[{"name":"Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center , Los Angeles, CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1634-9069","authenticated-orcid":false,"given":"Jonathan","family":"Kaye","sequence":"additional","affiliation":[{"name":"Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center , Los Angeles, CA"},{"name":"Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center , Los Angeles, CA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,4,28]]},"reference":[{"key":"2025021008065731200_r1","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/ni.3168","article-title":"The development of innate lymphoid cells requires TOX-dependent generation of a common innate lymphoid cell progenitor","volume":"16","author":"Seehus","year":"2015","journal-title":"Nat. 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