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U.S.A."],"published-print":{"date-parts":[[2021,10,5]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>\n                    CRBN, a substrate receptor of CUL4-RBX1-DDB1-CRBN (CRL4\n                    <jats:sup>CRBN<\/jats:sup>\n                    ) E3 ubiquitin ligase, is a direct target for thalidomide teratogenicity and antitumor activity of immunomodulatory drugs (IMiDs) in multiple myeloma (MM) and other hematologic malignancies. IMiDs bind CRBN to recruit neosubstrates for ubiquitylation and subsequent degradation. However, it is not known whether a deubiquitinating enzyme might be involved in this process. The present study revealed that USP15 antagonizes CRL4\n                    <jats:sup>CRBN<\/jats:sup>\n                    -mediated ubiquitylation of natural substrate glutamine synthetase and neosubstrates, thereby preventing their degradation. Targeting USP15 sensitizes IMiD-resistant MM cells to IMiDs by promoting degradation of neosubstrates. These results suggest USP15 protein expression as a predictive biomarker of response or resistance to IMiDs and highlight the potential of USP15 as a key cancer drug target.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2111391118","type":"journal-article","created":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T17:24:05Z","timestamp":1632849845000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":47,"title":["USP15 antagonizes CRL4\n                    <sup>CRBN<\/sup>\n                    -mediated ubiquitylation of glutamine synthetase and neosubstrates"],"prefix":"10.1073","volume":"118","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9114-7766","authenticated-orcid":false,"given":"Thang Van","family":"Nguyen","sequence":"first","affiliation":[{"name":"Center for Precision Medicine, Department of Medicine, University of Missouri, Columbia, MO 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