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N. B. Caberoy, G. Alvarado, W. Li; Mertk as a Common Phagocytic Receptor for Tubby and Tulp1 to Facilitate RPE Phagocytosis. Invest. Ophthalmol. Vis. Sci. 2010;51(13):500.
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© ARVO (1962-2015); The Authors (2016-present)
Mutations in tubby or tubby-like protein 1 (Tulp1) cause retinal degeneration with undefined molecular mechanisms. Both proteins have been recently identified as novel eat-me signals to facilitate retinal pigment epithelium (RPE) phagocytosis by a new strategy of phagocytosis-based functional cloning. The purpose of this study is to further characterize tubby and Tulp1 as novel eat-me signals by elucidating their phagocytic receptors and signaling cascades.
Binding of tubby and Tulp1 to phagocytic receptor MerTK was analyzed by co-immunoprecipitation. MerTK activation was investigated by receptor phosphorylation. MerTK-dependent signaling of non-muscle myosin II activation was characterized by immunohistochemistry. Receptor-binding domains of Tulp1 were delineated by mutation and deletion analyses.
Tubby and Tulp1 bound to MerTK, while Tulp1 additionally interacted with Axl and Tyro3 in the same receptor tyrosine kinase subfamily. Tubby and Tulp1 induced MerTK phosphorylation, MerTK-dependent myosin II redistribution and colocalization with phagosomes. Mutation analyses revealed five minimal phagocytosis determinants (MPDs) with a consensus motif in the N-terminus of Tulp1, which were essential for Tulp1-mediated MerTK binding, receptor activation and RPE phagocytosis. Tubby and Tulp1 bound to both MerTK and phagocytosis preys to facilitate phagocytosis that was blocked by excessive amount of soluble MerTK extracellular domain (Mer-Fc), tubby N-terminal domain (Tubby-N) or Tulp1-N.
These data demonstrated that tubby and Tulp1 are novel MerTK ligands that function as bridging molecules to facilitate RPE phagocytosis. These results provide in-depth understanding of RPE phagocyte biology and its regulation by tubby and Tulp1.
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