OTUD3: A Lys6 and Lys63 Specific Deubiquitinase in Early Vertebrate Development

Ubiquitination and deubiquitylation regulate essential cellular processes and involve hundreds of sequentially acting enzymes, many of which are barely understood. OTUD3 is an evolutionarily highly conserved deubiquitinase involved in many aspects of cellular homeostasis. However, its biochemical properties and physiological role during development are poorly understood. Here, we report on the expression of OTUD3 in human tissue samples where it appears prominently in those of neuronal origin. In cells, OTUD3 is present in the cytoplasm where it can bind to microtubules. Interestingly, we found that OTUD3 cleaves preferentially at K6 and K63, i.e., poly-ubiquitin linkages that are not primarily involved in protein degradation. We employed Xenopus embryos to study the consequences of suppressing otud3 function during early neural development. We found that Otud3 deficiency led to impaired formation of cranial and particularly of cranial neural crest-derived structures as well as movement defects. Thus, OTUD3 appears as a neuronally enriched deubiquitinase that is involved in the proper development of the neural system.