{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T06:23:51Z","timestamp":1787207031591,"version":"build-2736575974"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neural Circuits"],"abstract":"<jats:p>\n                    Sterile alpha and TIR motif-containing protein 1 (SARM1) is an enzyme that cleaves nicotinamide adenine dinucleotide (NAD\n                    <jats:sup>+<\/jats:sup>\n                    ) and plays a role in disrupting neural circuits through axon degeneration and cell death. SARM1 is activated by changes in the nicotinamide mononucleotide (NMN)\/NAD\n                    <jats:sup>+<\/jats:sup>\n                    ratio and by various post-translational modifications, but its complete regulatory mechanism remains poorly understood. Here, we report that tripartite motif-containing protein 32 (TRIM32) activates SARM1 through specific ubiquitination triggered by anticancer drug treatment. TRIM32 promotes the attachment of Lys27-linked ubiquitin chains to Lys173 and Lys375 within the ARM domain, which is an autoinhibitory region of SARM1. This ubiquitination by TRIM32 increases SARM1\u2019s NAD\n                    <jats:sup>+<\/jats:sup>\n                    -cleaving catalytic activity and enhances its ability to induce neurite degeneration and cell death. A mutant form of TRIM32 lacking the enzymatically active RING domain fails to promote SARM1 ubiquitination, and reducing TRIM32 levels decreases SARM1 ubiquitination. Additionally, ubiquitin-specific peptidase 13 (USP13), a known negative regulator of SARM1, can deubiquitinate SARM1. These findings suggest that TRIM32 is a key regulator of axon degeneration and cell death through its ubiquitination of SARM1.\n                  <\/jats:p>","DOI":"10.3389\/fncir.2026.1842408","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T05:28:34Z","timestamp":1787203714000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["New mechanistic insight into SARM1 activation: TRIM32-mediated ubiquitination is a key lever that actuates SARM1\u2019s catalytic action, leading to axon degeneration and cell death"],"prefix":"10.3389","volume":"20","author":[{"given":"Hitoshi","family":"Murata","sequence":"first","affiliation":[{"name":"Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences","place":["Okayama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nahoko","family":"Tomonobu","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences","place":["Okayama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken-ichi","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences","place":["Okayama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rie","family":"Kinoshita","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences","place":["Okayama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masakiyo","family":"Sakaguchi","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences","place":["Okayama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"3226","DOI":"10.1093\/brain\/awab184","article-title":"Pharmacological SARM1 inhibition protects axon structure and function in paclitaxel-induced peripheral neuropathy","volume":"144","author":"Bosanac","year":"2021","journal-title":"Brain"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"3711","DOI":"10.1016\/j.neuron.2022.08.017","article-title":"Uncompetitive, adduct-forming SARM1 inhibitors are neuroprotective in preclinical models of nerve injury and disease","volume":"110","author":"Bratkowski","year":"2022","journal-title":"Neuron"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"107999","DOI":"10.1016\/j.celrep.2020.107999","article-title":"Structural and mechanistic regulation of the pro-degenerative NAD hydrolase SARM1","volume":"32","author":"Bratkowski","year":"2020","journal-title":"Cell Rep."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1412","DOI":"10.1016\/j.immuni.2019.04.005","article-title":"Cell survival and cytokine release after inflammasome activation is regulated by the toll-IL-1R protein SARM","volume":"50","author":"Carty","year":"2019","journal-title":"Immunity"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"2123","DOI":"10.3390\/biomedicines12092123","article-title":"Characterization of novel SARM1 inhibitors for the treatment of chemotherapy-induced peripheral neuropathy","volume":"12","author":"Chen","year":"2024","journal-title":"Biomedicine"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"e2517110123","DOI":"10.1073\/pnas.2517110123","article-title":"Hyperglycemia promotes SIRT3-mediated deacetylation of SARM1 to exacerbate diabetic peripheral neuropathy in mice","volume":"123","author":"Chen","year":"2026","journal-title":"Proc. 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Neurobiol."},{"key":"ref13","first-page":"1118","article-title":"SARM1 is a metabolic sensor activated by an increased NMN\/NAD(+) ratio to trigger axon degeneration","volume-title":"Neuron","author":"Figley","year":"2021"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"3092","DOI":"10.1093\/brain\/aww251","article-title":"Prevention of vincristine-induced peripheral neuropathy by genetic deletion of SARM1 in mice","volume":"139","author":"Geisler","year":"2016","journal-title":"Brain"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"13569","DOI":"10.1523\/JNEUROSCI.1197-13.2013","article-title":"Sarm1-mediated axon degeneration requires both SAM and TIR interactions","volume":"33","author":"Gerdts","year":"2013","journal-title":"J. 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