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Here, we identified DNAJB6, an Hsp40 (DnaJ) co-chaperone, as a substrate of the circadian E3 ligase FBXL21. FBXL21 mediated the ubiquitination-dependent proteasomal degradation of both DNAJB6 and its client proteins including Desmin; causative mutations of DNAJB6 in myopathies, however, rendered resistance to FBXL21-directed degradation.\n                  <jats:italic>Fbxl21<\/jats:italic>\n                  KO C2C12 cells displayed aberrant accumulation of Desmin, and showed aggravated cytoplasmic accumulation of TDP-43, another DNAJB6 client protein, in heat shock response. Under timed exercise as a physiological stressor, WT mice displayed robust diurnal rhythms in the levels of stress granule markers (G3BP1 and FUS) and TDP-43 as a function of exercise timing. In contrast, the\n                  <jats:italic>Fbxl21<\/jats:italic>\n                  hypomorph\n                  <jats:italic>Psttm<\/jats:italic>\n                  mutant mice showed elevated expression of these proteins without exercise, which was exacerbated under exercise-induced stress conditions; importantly, these abnormalities were rescued by skeletal muscle-specific FBXL21 expression. Our study elucidates a novel diurnal regulatory mechanism of skeletal muscle proteostasis via FBXL21 as a chaperone-linked E3 ligase, highlighting the FBXL21-DNAJB6 axis as a potential therapeutic target for myopathies.\n                <\/jats:p>","DOI":"10.64898\/2026.05.20.726545","type":"posted-content","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T12:30:16Z","timestamp":1779453016000},"source":"Crossref","is-referenced-by-count":0,"title":["FBXL21 regulates diurnal proteostasis and stress response by targeting DNAJB6 and client proteins"],"prefix":"10.64898","author":[{"given":"Ji Ye","family":"Lim","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin St., Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaebok","family":"Wi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin St., Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marvin","family":"Wirianto","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin St., Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chorong","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin St., Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun Young","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin St., Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin St., Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sehyun","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin St., Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin","family":"Eckel-Mahan","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, TX, 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung Yun","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karyn A.","family":"Esser","sequence":"additional","affiliation":[{"name":"Department of Physiology and Aging, The University of Florida College of Medicine, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2464-5474","authenticated-orcid":false,"given":"Zheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin St., Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung-Hee","family":"Yoo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin St., Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"issue":"Suppl 1","key":"2026052601350733000_2026.05.20.726545v1.1","first-page":"S46","article-title":"Ticking for Metabolic Health: The Skeletal-Muscle Clocks","volume":"28","year":"2020","journal-title":"Obesity (Silver Spring)"},{"key":"2026052601350733000_2026.05.20.726545v1.2","doi-asserted-by":"publisher","DOI":"10.1113\/JP271436"},{"key":"2026052601350733000_2026.05.20.726545v1.3","doi-asserted-by":"publisher","DOI":"10.1177\/0748730414561638"},{"key":"2026052601350733000_2026.05.20.726545v1.4","doi-asserted-by":"publisher","DOI":"10.1097\/JES.0b013e3182a58a70"},{"key":"2026052601350733000_2026.05.20.726545v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/nrg.2016.150"},{"key":"2026052601350733000_2026.05.20.726545v1.6","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1408886111"},{"key":"2026052601350733000_2026.05.20.726545v1.7","doi-asserted-by":"crossref","unstructured":"Mure LS , Le HD , Benegiamo G , et al. 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