The retinol-binding protein receptor STRA6 and melanin cooperatively sustain retinoid signaling and outer blood-retinal barrier integrity

Disruption of the outer blood-retinal barrier (oBRB) is a central feature of retinal degenerative diseases, including age-related macular degeneration, yet the molecular mechanisms maintaining this barrier in the adult eye remain poorly defined. STRA6, a high-affinity receptor for retinol-binding protein (RBP4), mediates vitamin A uptake at the basolateral membrane of the retinal pigment epithelium (RPE), while melanin protects ocular retinoid stores from photooxidative stress. We previously showed that STRA6 deficiency leads to downregulation of junctional proteins in the RPE. Here, we demonstrate that STRA6 and melanin act synergistically to preserve the integrity of the oBRB. In albino Stra6 knockout mice, ocular retinoid levels were severely reduced despite normal circulating retinol levels, and dietary vitamin A delivered via chylomicrons failed to compensate for the loss of RBP4-mediated transport. This led to a functional impairment of both rod- and cone-mediated responses, even under vitamin A-sufficient conditions. Mice also showed downregulated tight junction proteins (ZO-1, Claudin-1, Claudin-3), RPE disorganization, barrier leakage, and immune cell infiltration into the subretinal space. These defects were further exacerbated under dietary vitamin A restriction. Importantly, systemic treatment with the pan-retinoic acid receptor (RAR) agonist TTNPB restored junctional gene expression and oBRB function in Stra6^-/- mice, providing evidence that barrier failure arises from impaired retinoid signaling rather than structural loss of STRA6 and melanin. These findings define a novel role for retinoic acid in sustaining RPE barrier function and highlight the combined importance of STRA6-mediated transport and melanin-dependent photoprotection in retinal homeostasis.