Tubby and tubby-like protein 1 are new MerTK ligands for phagocytosis

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Abstract
Tubby and tubby‐like protein 1 (Tulp1) are newly identified phagocytosis ligands to facilitate retinal pigment epithelium (RPE) and macrophage phagocytosis. Both proteins without classical signal peptide have been demonstrated with unconventional secretion. Here, we characterized them as novel MerTK ligands to facilitate phagocytosis. Tulp1 interacts with Tyro3, Axl and MerTK of the TAM receptor tyrosine kinase subfamily, whereas tubby binds only to MerTK. Excessive soluble MerTK extracellular domain blocked tubby‐ or Tulp1‐mediated phagocytosis. Both ligands induced MerTK activation with receptor phosphorylation and signalling cascade, including non‐muscle myosin II redistribution and co‐localization with phagosomes. Tubby and Tulp1 are bridging molecules with their N‐terminal region as MerTK‐binding domain and C‐terminal region as phagocytosis prey‐binding domain (PPBD). Five minimal phagocytic determinants (MPDs) of K/R(X)1–2KKK in Tulp1 N‐terminus were defined as essential motifs for MerTK binding, receptor phosphorylation and phagocytosis. PPBD was mapped to the highly conserved 54 amino acids at the C‐terminal end of tubby and Tulp1. These data suggest that tubby and Tulp1 are novel bridging molecules to facilitate phagocytosis through MerTK.