Hook1 is a coiled-coil protein that has a role in tethering microtubules and cargo during clathrin-independent endocytosis. Hook1 is involved in the sorting of cargo proteins, such as CD98 and CD147, into recycling endosomes, which ensures that these proteins avoid transport to lysosomes for degradation. It is unclear, however, how endocytosed Hook1-mediated cargo proteins are recycled back to the plasma membrane. Now, Hiromichi Shirataki and colleagues (Higashi et al. 2022) identify the protein γ-taxilin as an important negative regulator of Hook1. Knowing that α-taxilin has a role in intracellular vesicle trafficking, the authors postulate that another member of the family, γ-taxilin, might have a similar role. Using yeast two-hybrid screening, they identify Hook1 as a novel binding partner of γ-taxilin and show that γ-taxilin binds to Hook1 competitively with CD98. Depletion of γ-taxilin promotes the formation of CD98- or CD147-containing tubular recycling endosomes and a faster rate of recycling of these cargo proteins back to the plasma membrane; depletion also promotes CD147-mediated cell spreading. Overexpression of γ-taxilin, however, inhibits CD98-positive tubular endosome formation. Finally, the authors demonstrate that γ-taxilin competes with CD98 and CD147 for binding to the C-terminal region of Hook1. Based on these findings, the authors suggest that γ-taxilin negatively regulates the sorting into tubular endosomes of Hook1-mediated cargo proteins by inhibiting the interaction between them and Hook1. These data make an important contribution to the mechanistic understanding of endosomal sorting of cargo proteins.
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