---
title: "RNF216 substrate profiling reveals a translation-linked OTUD4 regulatory axis in neurons"
id: "biorxiv-1-substrate-profiling-of-rnf216-uncovers-a-translation-linked-otud4-regulatory"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-1-substrate-profiling-of-rnf216-uncovers-a-translation-linked-otud4-regulatory"
content_type: "clinical_feed_article"
specialty: "Neurology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.08.26.747332v1?rss=1"
published_at: "2026-08-30T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# RNF216 substrate profiling reveals a translation-linked OTUD4 regulatory axis in neurons
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-1-substrate-profiling-of-rnf216-uncovers-a-translation-linked-otud4-regulatory
- **Specialty:** [Neurology](https://medichelpline.com/clinical-feed/neurology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.08.26.747332v1?rss=1)
- **Published At:** 2026-08-30T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- The study used an orthogonal ubiquitin transfer (OUT) platform in neuronal cells to identify substrates of the E3 ubiquitin ligase **RNF216**. - Key substrates captured included the deubiquitinating enzyme **OTUD4** (itself mutated in Gordon Holmes syndrome) and the neuronal translational repressor **FMRP**. - RNF216 predominantly generates **K6-linked** ubiquitin chains on OTUD4, targeting OTUD4 for proteasomal degradation and producing donut-shaped OTUD4 structures in neurons. - OTUD4 reciprocally removes ubiquitin from RNF216 and from FMRP, indicating a bidirectional regulatory relationship between ligase and DUB. - Substrate analysis showed enrichment for proteins involved in **protein synthesis**, implicating RNF216-OTUD4 interactions in translational control. - Experimental perturbation altered cellular translation: RNF216 expression increased protein synthesis rates across cell types, while genetic deletion of Rnf216 reduced dendritic development in neurons. - The authors propose that RNF216 and OTUD4 balance rates of protein synthesis and degradation, and that disease-associated mutations in RNF216 or OTUD4 may disrupt this balance and contribute to neurodegeneration in **Gordon Holmes syndrome**. - Funding sources and competing interest: no competing interests declared; study supported by multiple NIH and NSF grants as listed in the source.
## Clinical Analysis & Structured Key Points
Substrate Profiling of RNF216 Uncovers a Translation-Linked OTUD4 Regulatory Axis | bioRxiv Skip to main content New Results Substrate Profiling of RNF216 Uncovers a Translation-Linked OTUD4 Regulatory Axis View ORCID Profile Wei Wei , Ruochuan Liu , Jing Zhang , View ORCID Profile Shu Liu , Antoinette J Charles , Devash G Asati , View ORCID Profile Zachary D Allen , Delance Wright , Kangli Peng , Ellissa Krekeler , View ORCID Profile Nima Mosammaparast , View ORCID Profile Jun Yin , View ORCID Profile Angela M Mabb doi: https://doi.org/10.64898/2026.08.26.747332 Wei Wei 1 Georgia State University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Wei Wei Ruochuan Liu 1 Georgia State University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jing Zhang 1 Georgia State University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Shu Liu 1 Georgia State University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Shu Liu Antoinette J Charles 1 Georgia State University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Devash G Asati 1 Georgia State University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Zachary D Allen 1 Georgia State University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Zachary D Allen Delance Wright 1 Georgia State University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kangli Peng 1 Georgia State University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ellissa Krekeler 2 Washington University in St. Louis Find this author on Google Scholar Find this author on PubMed Search for this author on this site Nima Mosammaparast 2 Washington University in St. Louis Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Nima Mosammaparast Jun Yin 1 Georgia State University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Jun Yin Angela M Mabb 1 Georgia State University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Angela M Mabb For correspondence: amabb{at}gsu.edu Abstract Info/History Metrics Supplementary material Preview PDF Abstract Mutations in the E3 Ubiquitin (Ub) ligase RNF216 cause Gordon Holmes syndrome (GHS), a neurodegenerative disorder accompanied by neuroendocrine disruption. We developed an orthogonal ubiquitin transfer (OUT) platform to capture RNF216 substrates in neuronal cells and identified OTUD4, a deubiquitinating enzyme (DUB) mutated in GHS, and FMRP, a neuronal-enriched translational repressor. RNF216 predominantly synthesizes K6-linked Ub chains on OTUD4 to induce its degradation, forming donut-shaped structures in neurons. In return, OTUD4 removes the ubiquitination of RNF216 and FMRP. Analysis of RNF216 substrates revealed biological functions regulating protein synthesis, a shared function of the OTUD4-RNF216 substrate interaction network. Indeed, RNF216 expression increased protein synthesis rates in different cell types while Rnf216 deletion decreased dendritic development in neurons. Overall, our findings show that RNF216 and OTUD4 balance rates of protein synthesis and degradation and suggest GHS-related mutations in RNF216 or OTUD4 may offset this balance, triggering neurodegeneration. Competing Interest Statement The authors have declared no competing interest. Funder Information Declared NIH/NINDS , R01NS136464 , R21NS116760 NSF CAREER , 2047700 NIH/NIGMS , R01 GM160854 NIH/NCI , R01 CA282733 , P01 CA092584 Brains & Behavior Seed Grant Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Back to top Previous Posted August 30, 2026. Download PDF Supplementary Material Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. 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Share Substrate Profiling of RNF216 Uncovers a Translation-Linked OTUD4 Regulatory Axis Wei Wei , Ruochuan Liu , Jing Zhang , Shu Liu , Antoinette J Charles , Devash G Asati , Zachary D Allen , Delance Wright , Kangli Peng , Ellissa Krekeler , Nima Mosammaparast , Jun Yin , Angela M Mabb bioRxiv 2026.08.26.747332; doi: https://doi.org/10.64898/2026.08.26.747332 Share This Article: Copy Citation Tools Substrate Profiling of RNF216 Uncovers a Translation-Linked OTUD4 Regulatory Axis Wei Wei , Ruochuan Liu , Jing Zhang , Shu Liu , Antoinette J Charles , Devash G Asati , Zachary D Allen , Delance Wright , Kangli Peng , Ellissa Krekeler , Nima Mosammaparast , Jun Yin , Angela M Mabb bioRxiv 2026.08.26.747332; doi: https://doi.org/10.64898/2026.08.26.747332 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Areas All Articles Animal Behavior and Cognition (7945) Biochemistry (18565) Bioengineering (14718) Bioinformatics (43990) Biophysics (22383) Cancer Biology (19500) Cell Biology (26670) Clinical Trials (138) Developmental Biology (13855) Ecology (20805) Epidemiology (2067) Evolutionary Biology (25252) Genetics (16068) Genomics (23353) Immunology (18529) Microbiology (42099) Molecular Biology (17889) Neuroscience (92585) Paleontology (691) Pathology (2960) Pharmacology and Toxicology (5051) Physiology (8030) Plant Biology (15847) Scientific Communication and Education (2090) Synthetic Biology (4523) Systems Biology (10156) Zoology (2368)
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