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Abstract
The C-terminal Eps15 homology domain-containing protein, EHD1, is an important regulator of receptor recycling back to the plasma membrane. In addition to its vesicular localization, EHD1 also localizes to a unique array of tubular membrane structures that emanate from the endocytic recycling compartment. While these structures have been described over 7 years ago, addressing their lipid composition and physiological function has been challenging. Moreover, it was not known whether EHD1 itself induces tubule formation, or whether it localizes to pre-existing tubular membrane structures. We have demonstrated that in vivo, EHD1 localizes to pre-existing tubular membranes that contain both phosphatidylinositol-4-phosphate and phosphatidylinositol-(4,5)-bisphosphate. Moreover, we have determined that ‘non-tubular’ EHD1 mutants with a single residue substitution do not efficiently facilitate receptor recycling. Our data suggest that EHD1-associated tubules are required for efficient recycling and we propose models that describe the potential mechanisms by which EHD1 functions.
Acknowledgements
We gratefully acknowledge the support of NIH grants GM074876 and P20 RR018759 (SC), GM072631 (PLS), and the American Heart Association (MS).
Figures and Tables
Figure 1 Potential models depicting mechanisms of EHD1-mediated recycling from the ERC. (A) EHD1 dimers in their ATP-bound state are recruited to the PtdIns(4)P-enriched tubular membranes of the ERC. EHD1 can then either directly or indirectly associate with cargo vesicles (via an unknown protein(s) such as a Rab effector) coming from the early endosome and provide a platform for association of motor proteins that might drive recycling vesicles back to the plasma membrane. (B) A second proposed mechanism for EHD1-mediated recycling is that ATP-bound EHD1 associates with tubular PtdIns(4)P-enriched membranes. Once on these structures, EHD1 utilizes its intrinsic ATPase activity and acts as a ‘pinchase’ to promote membrane fission of the vesicles budding from the ERC tubules. These pinched-off cargo vesicles can then be carried back to the plasma membrane by the motor proteins as described above.
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