{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T15:32:35Z","timestamp":1781105555269,"version":"3.54.1"},"reference-count":40,"publisher":"National Academy of Sciences","issue":"32","license":[{"start":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T00:00:00Z","timestamp":1754524800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS | NIH","doi-asserted-by":"publisher","award":["AI162656"],"award-info":[{"award-number":["AI162656"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | NIH","doi-asserted-by":"publisher","award":["AG065532"],"award-info":[{"award-number":["AG065532"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | NIH","doi-asserted-by":"publisher","award":["HL007344"],"award-info":[{"award-number":["HL007344"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | NIH","doi-asserted-by":"publisher","award":["AI007260"],"award-info":[{"award-number":["AI007260"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","award":["IK6 BX005392"],"award-info":[{"award-number":["IK6 BX005392"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,8,12]]},"abstract":"<jats:p>\n                    TNF receptor-associated factor 3 (TRAF3) is a signaling adaptor protein that is ubiquitously expressed but has highly distinct cell type\u2013specific functions. TRAF3 plays critical roles in restraint of B lymphocyte activation, differentiation, and homeostatic survival. Consistent with such roles, loss-of-function mutations in\n                    <jats:italic toggle=\"yes\">TRAF3<\/jats:italic>\n                    have long been found in various human B cell malignancies. Mice lacking TRAF3 specifically in B cells have autoimmune manifestations, lymphadenopathy, and increased incidence of B cell lymphomas. More recently, human patients with germline\n                    <jats:italic toggle=\"yes\">TRAF3<\/jats:italic>\n                    mutations leading to haploinsufficiency have been reported; the phenotypes of these patients show striking similarities with those of mice with TRAF3-deficient B cells. This raises the important knowledge gap of how relative quantity of TRAF3 protein regulates B cells. To address this question, we investigated the effect of decreased B cell TRAF3 using mice whose B cells are heterozygous for loss of\n                    <jats:italic toggle=\"yes\">Traf3<\/jats:italic>\n                    .\n                    <jats:italic toggle=\"yes\">Traf3<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    B cells displayed multiple functional abnormalities, to an extent intermediate between\n                    <jats:italic toggle=\"yes\">\n                      Traf3\n                      <jats:sup>+\/+<\/jats:sup>\n                    <\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">\n                      Traf3\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    B cells, indicating a striking dose\u2013response of B cells to relative quantities of TRAF3. Additionally, B cell TRAF3 protein\u2014but not transcript\u2014was reduced in B cells from normal aged mice and humans, consistent with increased occurrence of both B cell hyperactivity and B cell malignancies in older populations. Treatment of aged mice with a proteasome inhibitor restored the level of B cell TRAF3, suggesting age-related chronic signaling through receptors that lead to TRAF3 degradation. Thus, relative levels of B cell TRAF3 protein have important biological impacts on B cell function.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2507217122","type":"journal-article","created":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T15:35:16Z","timestamp":1754580916000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["Reduction of TRAF3 by heterozygosity or aging impacts B cell function"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1355-0576","authenticated-orcid":false,"given":"Emma L.","family":"Hornick","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Iowa","place":["Iowa City"]},{"name":"Holden Comprehensive Cancer Center, University of Iowa","place":["Iowa City"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyp","family":"Oxley","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Iowa","place":["Iowa City"]},{"name":"Holden Comprehensive Cancer Center, University of Iowa","place":["Iowa City"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1019-8772","authenticated-orcid":false,"given":"Nathaniel","family":"Wieting","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Iowa","place":["Iowa City"]},{"name":"Holden Comprehensive Cancer Center, University of Iowa","place":["Iowa City"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6634-3717","authenticated-orcid":false,"given":"Emma","family":"Treco","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Iowa","place":["Iowa City"]},{"name":"Holden Comprehensive Cancer Center, University of Iowa","place":["Iowa 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