Ovarian tumour domain-containing protein 4 (OTUD4) is a deubiquitylase mutated in the rare Gordon Holmes syndrome, a disease characterised by a number of neuronal defects. However, little is known about the molecular functions of OTUD4. In their study, Meike Broemer and colleagues (Das et al., 2019) address this knowledge gap by searching for OTUD4 interaction partners in mouse brain lysates. They show that OTUD4 not only interacts with many RNA-binding proteins and stress granule components, but also binds to RNA itself. Indeed, upon heat-shock or oxidative stress, OTUD4 forms distinct granules that colocalise with stress granules. OTUD4 also colocalises with neuronal RNA granules, which allow the transport of untranslated mRNA along the axon. The authors further find that, upon oxidative or heat stress, knockdown of OTUD4 causes stress granules to be smaller and more numerous. Additionally, these cells undergo apoptosis at a higher rate, indicating that cells succumb to stress-induced death more easily in the absence of OTUD4. Finally, the authors demonstrate that OTUD4 co-sediments with polysomes upon sucrose gradient fractionation and that OTUD4 knockdown reduces mRNA translation. Taken together, these results indicate that OTUD4 plays a multifaceted role during stress granule formation and in regulating mRNA translation, possibly to ensure timely protein production in neurons.

• © 2019. Published by The Company of Biologists Ltd