Postprenylation processing of phosphodiesterase is critical for robust cone photoreceptor response.

In mammalian photoreceptors, several phototransduction proteins undergo prenylation, a posttranslational lipid modification. These prenylated proteins are then processed by RAS-converting enzyme 1 (RCE1), which cleaves the final three amino acids. RCE1-mediated endoproteolysis is critical for maintaining rod photoreceptor structure and function; its early loss in the retina causes rapid degeneration and disrupts the trafficking of rod phosphodiesterase 6 (PDE6). However, the early and rapid degeneration has limited our understanding of RCE1's role in cones. To address this challenge, we developed a cone-specific Rce1 knockout model. Unlike in the retina-wide knockout, cone survival was unaffected. Nonetheless, electroretinography (ERG) revealed a significant reduction in cone function. Double-flash and flicker ERG further demonstrated impaired recovery in cones lacking RCE1. Despite unchanged transcript levels, cone PDE6 protein was reduced by 90%; the residual protein, though correctly assembled, failed to associate with membranes and instead accumulated in the inner segment. In contrast, the localization and abundance of other prenylated proteins, including rhodopsin kinase and transducin, were unaffected. These findings demonstrate that RCE1-dependent postprenylation processing (PPP) is specifically required for maintaining PDE6 membrane association and levels in cones. As a result, the sensitivity and recovery of cone photoreceptor responses are compromised in the absence of RCE1.