Axin1 stabilizes S-opsin and maintains cone photoreceptor survival by inhibiting GSK3β activity

TL;DR

Axin1 helps stabilize S-opsin and prevents cone photoreceptor death by inhibiting GSK3β activity in the retina.

Contribution

Axin1's role in retinal phototransduction and photoreceptor survival via GSK3β inhibition is newly established.

Findings

Axin1 is essential for S-opsin localization in photoreceptor outer segments.

Axin1 deficiency causes cone photoreceptor loss and ER stress.

Axin1 inhibition of GSK3β reduces ER stress-induced apoptosis.

Abstract

To ensure high phototransduction efficiency in the retina, the precise subcellular localization of signaling molecules must be tightly orchestrated by scaffold proteins. Aberrant localization of these scaffold proteins not only disrupts the transition of photoelectrical signals but also triggers endoplasmic reticulum (ER) stress, which leads to photoreceptor apoptosis. However, it is unknown how these proteins are localized to specific subcellular compartments of photoreceptors or how protein mislocalization is coupled with apoptotic signaling. Herein, we observed a specific spatiotemporal expression pattern of the scaffold protein, Axin1, in the mouse retina. We found that Axin1 is essential for the retinal localization of S-opsin chromoprotein in the outer segment of photoreceptors. Moreover, retinal Axin1 deficiency disrupts light perception, accompanied by cone photoreceptor loss and ER stress. In addition, knockdown of Axin1 exacerbates ER stress-induced apoptosis of cone-derived 661W cells. Consistently, pharmacological elevation of Axin1 protein level alleviates tunicamycin-induced ER stress and apoptosis via inhibition of GSK3β activity. Thus, our findings demonstrate that Axin1 plays a pivotal role in organizing the phototransduction complex and ensuring photoreceptor survival in the retina.

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