Epsin1 enforces a condensation-dependent checkpoint for ubiquitylated cargo during clathrin-mediated endocytosis

Susovan Sarkar, Hao-Yang Liu, Feng Yuan, Brandon T. Malady, Liping Wang, Eileen M. Lafer, Jessica Perez, Jon M. Huibregtse and Jeanne C. Stachowiak ()
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Susovan Sarkar: The University of Texas at Austin
Hao-Yang Liu: The University of Texas at Austin
Feng Yuan: The University of Texas at Austin
Brandon T. Malady: The University of Texas at Austin
Liping Wang: Science Center at San Antonio
Eileen M. Lafer: Science Center at San Antonio
Jessica Perez: The University of Texas at Austin
Jon M. Huibregtse: The University of Texas at Austin
Jeanne C. Stachowiak: The University of Texas at Austin

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Clathrin-mediated endocytosis internalizes proteins and lipids from the cell surface. A flexible condensate of initiator proteins catalyzes assembly of clathrin-coated vesicles in diverse organisms. Here we reveal that an endocytic adaptor protein, Epsin1, conditionally stabilizes this network, creating a cargo-dependent endocytic checkpoint. Epsin1 recruits ubiquitylated cargo to endocytic sites. Using in vitro assays, we demonstrate that Epsin1 destabilizes condensation of initiator proteins in the absence of ubiquitin. However, when polyubiquitin is present, Epsin1 binds to both ubiquitin and initiator proteins, stabilizing condensation. Similarly, in mammalian cells, endocytosis is disrupted by removal of either ubiquitin or Epsin1. When both components are removed simultaneously, endocytic defects are largely rescued, although the ability to preferentially internalize ubiquitylated cargo is lost. These results suggest that Epsin1 tunes protein condensation to internalize ubiquitylated cargo. More broadly, these findings illustrate how a balance of attractive and repulsive molecular interactions can exert dynamic control over cellular events.

Date: 2025
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DOI: 10.1038/s41467-025-63238-z

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