Dysfunction of Unc119, a Transducin-Binding Protein, Leads to Cone-Rod Dystrophy through Activating JAK-Stat and...

Transducin is a heterotrimeric G-protein that is a component of the phototransduction cascade in rod and cone photoreceptor cells of the retina. Gnat1, a rod-specific transducin α-subunit, regulates light/dark adaptation by changing its subcellular localization depending on light. Our previous study revealed that Gnat1 translocation in rod photoreceptor cells under light/dark conditions requires E3 ligase Klhl18-mediated ubiquitination and degradation of Unc119, a Gnat1-binding protein. A mutation in the human UNC119 gene is associated with cone-rod dystrophy (CRD); however, the underlying pathological mechanism remains unclear. In this study, we generated and analyzed Unc119-deficient (Unc119^-/- ) mice. We found that the retinas of Unc119^-/- mice of both sexes exhibited progressive photoreceptor degeneration, resembling CRD in humans. We also found that Unc119 interacts with Gnat2 in cone photoreceptor cells and that Unc119 is essential for the translocation of Gnat2 to the outer segment in cone photoreceptor cells. RNA-seq and subsequent bioinformatics analysis revealed the predicted activation of the JAK-STAT and NF-κB pathways in the Unc119^-/- retina. Treatment of Unc119^-/- mice with curcumin, an inhibitor of the JAK-STAT and NF-κB pathways, suppressed inflammation and cone photoreceptor cell degeneration in Unc119^-/- retinas. Furthermore, a human CRD-associated UNC119 mutant protein competitively inhibited the interaction between UNC119 and GNAT1 or GNAT2. Taken together, the current study suggests that UNC119 dysfunction leads to CRD by affecting the JAK-STAT and NF-κB pathways and may advance our understanding of the pathological mechanisms of CRD.