Essential role of the ubiquitin‐selective chaperone CDC48 in a poikilothermic vertebrate in cold adaptation

Cold‐inducible proteolytic degradation mechanism by the ubiquitin‐proteasome system (UPS) and autophagy was identified and characterized in zebrafish embryos. Previously, we identified a homolog of the mammalian valosin‐containing protein (VCP)/p97 and the yeast cell division cycle gene 48 (CDC48) as the major cold‐inducible protein in fish cells. We characterized that CDC48 was essential for cell growth and cell death functions in zebrafish embryonic ZE cultured cells under cold adaptable temperature between 15–20 °C (Imamura et al., 2003). In order to elucidate protective roles of CDC48 for cold acclimation and adaptation in poikilotherm, the protein degradation by UPS and autophagy mediated by CDC48 were examined in zebrafish embryos. When we compared between wild type and CDC48 deficiency embryos that were treated with antisense morpholino oligonucleotides, the CDC48 deficient embryos showed lethal defects in neuronal formation with apoptosis induction, ROS production and the accumulation of poly‐ubiquitinated proteins in the central nervous system under cold conditions. In these embryos, the degradation of poly‐ubiquitinated proteins was suppressed under cold condition at 15 °C. Thus, UPS functions were impaired in zebrafish embryos under cold conditions. In addition, autophagic marker protein p62 was accumulated in autophagosomes, whereas autolysosomes were not produced under cold conditions irrespective of the presence of CDC48. Therefore, CDC48 activated the UPS functions and promoted the neural development under cold conditions that caused autophagy impairment.