Oxygen-Sensing Protein Cysteamine Dioxygenase from Mandarin Fish Involved in the Arg/N-Degron Pathway and Rhabdovirus Infection.

Mammalia cysteamine (2-aminoethanethiol) dioxygenase (ADO) controls the stability of the regulator of G protein signaling 4 (RGS4) through the Cys branch of the Arg/N-degron pathway, thereby affecting the response of the body to hypoxia. However, the oxygen-sensing function of ADO remains unknown in teleost fish. Mandarin fish () is one of the most important freshwater economic fishes in China. As the scale of the rearing density continues to increase, hypoxia has become an important factor threatening the growth of mandarin fish. Herein, the molecular characterization, the oxygen-sensing enzyme function, and the role in virus infection of ADO from mandarin fish (ADO) were explored. Bioinformation analysis results showed that ADO had all the molecular foundations for achieving thiol dioxygenase function: three histidine residues coordinated with Fe(II), PCO/ADO domain, and a "jelly roll" β-barrel structure. The expression pattern analysis showed that was highly expressed in the immune-related tissues, liver, and kidneys and responded to hypoxia on the expression level. Protein degradation experiment results revealed that ADO could lead to the degradation of RGS4 protein through the Cys branch of the Arg/N-degron pathway. Furthermore, the expression levels of ADO responded to fish virus infection. ADO could significantly promote the replication of rhabdovirus, and this was associated with its thiol dioxygenase activity. These findings not only demonstrate ADO as an oxygen-sensing protein in teleost fish, but are also of considerable importance for clarifying the contribution of the mechanism of hypoxia to the outbreaks of fish viruses.