Substrate Profiling of RNF216 Uncovers a Translation-Linked OTUD4 Regulatory Axis

Mutations in the E3 Ubiquitin ligase RNF216 lead to Gordon Holmes syndrome (GHS), a neurodegenerative disorder characterized by neuroendocrine disruption. To study the RNF216 substrates, researchers developed an orthogonal ubiquitin transfer platform to capture these proteins in neuronal cells. This approach identified OTUD4, a deubiquitinating enzyme (DUB) mutated in GHS, as well as FMRP, a neuronal-enriched translational repressor.

RNF216 primarily synthesizes K6-linked Ub chains on OTUD4, resulting in its degradation and the formation of donut-shaped structures in neurons. Conversely, OTUD4 removes the ubiquitination of both RNF216 and FMRP. By analyzing RNF216 substrates, researchers discovered that their interaction network regulates protein synthesis, a shared function for both proteins.

Indeed, increased RNF216 expression leads to higher protein synthesis rates across various cell types, while Rnf216 deletion results in diminished dendritic development in neurons.

In summary, the study reveals that RNF216 and OTUD4 modulate protein synthesis and degradation rates, suggesting that GHS-related mutations in either RNF216 or OTUD4 may disrupt this balance, ultimately contributing to neurodegeneration.