Role of Melanoregulin in Photoreceptor Outer Segment Phagocytosis

Our previous studies document an essential role for melanoregulin (MREG) in lysosome‐dependent degradation of photoreceptor outer segments (POS) by the retinal pigment epithelium (RPE). Loss of MREG function results in delayed phagosome maturation leading to the accumulation of toxic debris associated with retinal degenerative disease. In these studies we test the hypothesis that MREG function is dependent on MerTK mediated phagocytosis of POSs. MREG localizes to RPE plasma membrane microdomains as well as intracellular punctate structures. MREG expression in RPE cells decreases in response to stimulation with Protein S, the ligand for MerTK, and increases at later time points. Using reciprocal co‐IPs and immunofluorescence analysis MREG was shown to interact with MerTK. MREG expression is also found to increase in RPE cells fed POS over a prolonged period, with a greater increase seen in response to UV‐oxidized POS, suggestive of a stress response. MREG colocalizes with late endosomal/lysosomal markers but not early endosomes. Knockdown of MREG expression by shRNA leads to fewer LAMP1 positive puncta suggesting a role in lysosomal formation. This implies that MREG regulates phagocytosis via the MerTK dependent signaling pathway which may involve the production of a second pool of lysosomes in response to excessive phagocytic challenge.