Substrate Profiling of RNF216 Uncovers a Translation-Linked OTUD4 Regulatory Axis
- 1Georgia State University
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 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.
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BibTeX
@misc{wei2026substrate,
title = {{Substrate Profiling of RNF216 Uncovers a Translation-Linked OTUD4 Regulatory Axis}},
author = {W. Wei and R. Liu and J. Zhang and S. Liu and A. J. Charles and D. G. Asati and Z. D. Allen and D. Wright and K. Peng and E. Krekeler and N. Mosammaparast and J. Yin and A. M. Mabb},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.26.747332},
url = {https://www.biorxiv.org/content/10.64898/2026.08.26.747332v2},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Substrate Profiling of RNF216 Uncovers a Translation-Linked OTUD4 Regulatory Axis
AU - W. Wei
AU - R. Liu
AU - J. Zhang
AU - S. Liu
AU - A. J. Charles
AU - D. G. Asati
AU - Z. D. Allen
AU - D. Wright
AU - K. Peng
AU - E. Krekeler
AU - N. Mosammaparast
AU - J. Yin
AU - A. M. Mabb
PY - 2026
DA - 2026/08/26
PB - bioRxiv
DO - 10.64898/2026.08.26.747332
UR - https://www.biorxiv.org/content/10.64898/2026.08.26.747332v2
AB - 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 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.
ER -