{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T19:11:43Z","timestamp":1790017903087,"version":"4.0.1"},"reference-count":56,"publisher":"National Academy of Sciences","issue":"45","license":[{"start":{"date-parts":[[2023,10,30]],"date-time":"2023-10-30T00:00:00Z","timestamp":1698624000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01GM148470"],"award-info":[{"award-number":["R01GM148470"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007052","name":"Memorial Sloan Kettering Cancer Center","doi-asserted-by":"crossref","award":["P30CA008748"],"award-info":[{"award-number":["P30CA008748"]}],"id":[{"id":"10.13039\/100007052","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2021R1A6A3A14038416"],"award-info":[{"award-number":["2021R1A6A3A14038416"]}],"id":[{"id":"10.13039\/501100003725","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":[[2023,11,7]]},"abstract":"<jats:p>\n                    Giant axonal neuropathy (GAN) is caused by mutations in the\n                    <jats:italic>GAN<\/jats:italic>\n                    gene encoding for gigaxonin (GIG), which functions as an adaptor of the CUL3-RBX1-GIG (CRL3\n                    <jats:sup>GIG<\/jats:sup>\n                    ) E3 ubiquitin ligase complex. The pathological hallmark of GAN is characterized by the accumulation of densely packed neurofilaments (NFs) in the axons. However, there are fundamental knowledge gaps in our understanding of the molecular mechanisms by which the ubiquitin\u2013proteasome system controls the homeostasis of NF proteins. Recently, the deubiquitylating enzyme USP15 was reported to play a crucial role in regulating ubiquitylation and proteasomal degradation of CRL4\n                    <jats:sup>CRBN<\/jats:sup>\n                    substrate proteins. Here, we report that the CRL3\n                    <jats:sup>GIG<\/jats:sup>\n                    \u2013USP15 pathway governs the destruction of NF proteins NEFL and INA. We identified a specific degron called NEFL\n                    <jats:sup>L12<\/jats:sup>\n                    degron for CRL3\n                    <jats:sup>GIG<\/jats:sup>\n                    . Notably, mutations in the C-terminal Kelch domain of GIG, represented by L309R, R545C, and C570Y, disrupted the binding of GIG to NEFL and INA, leading to the accumulation of these NF proteins. This accounts for the loss-of-function mutations in GAN patients. In addition to regulating NFs, CRL3\n                    <jats:sup>GIG<\/jats:sup>\n                    also controls actin filaments by directly targeting actin-filament-binding regulatory proteins TPM1, TPM2, TAGLN, and CNN2 for proteasomal degradation. Thus, our findings broadly impact the field by providing fundamental mechanistic insights into regulating extremely long-lived NF proteins NEFL and INA by the CRL3\n                    <jats:sup>GIG<\/jats:sup>\n                    \u2013USP15 pathway and offering previously unexplored therapeutic opportunities to treat GAN patients and other neurodegenerative diseases by explicitly targeting downstream substrates of CRL3\n                    <jats:sup>GIG<\/jats:sup>\n                    .\n                  <\/jats:p>","DOI":"10.1073\/pnas.2306395120","type":"journal-article","created":{"date-parts":[[2023,10,30]],"date-time":"2023-10-30T15:09:20Z","timestamp":1698678560000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":9,"title":["The CRL3\n                    <sup>gigaxonin<\/sup>\n                    ubiquitin ligase\u2013USP15 pathway governs the destruction of neurofilament proteins"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7397-8286","authenticated-orcid":false,"given":"Hyoung-Min","family":"Park","sequence":"first","affiliation":[{"name":"Biometrology Group, Korea Research Institute of Standards and Science, Daejeon 34113, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ly","family":"Le","sequence":"additional","affiliation":[{"name":"Division of Quantum Simulation and Optimization, SandboxAQ, New York, NY 10591"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thao T.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Gehrke Proteomics Center, Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO 65211"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ki Hong","family":"Nam","sequence":"additional","affiliation":[{"name":"Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4924-8520","authenticated-orcid":false,"given":"Alban","family":"Ordureau","sequence":"additional","affiliation":[{"name":"Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Eugene","family":"Lee","sequence":"additional","affiliation":[{"name":"Biometrology Group, Korea Research Institute of Standards and Science, Daejeon 34113, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9114-7766","authenticated-orcid":false,"given":"Thang Van","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Center for Precision Medicine, Department of Medicine, University of Missouri, Columbia, MO 65212"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,10,30]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-051910-094049"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.67.1.425"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2016.31"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1547"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-090120-013613"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2021.04.008"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2005-6-10-r82"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1056"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01959"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01985"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.24.10941-10953.2004"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2009.09.022"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.437996"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0060445"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI39894"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2148-7-164"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.104729"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2022.10.017"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00686905"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1542\/peds.49.6.894"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-510X(87)90019-0"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000101676.41505.A7"},{"key":"e_1_3_4_23_2","volume-title":"GeneReviews\u00ae","author":"Opal P.","year":"1993","unstructured":"P. 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