Yeast Endocytic Adaptor AP-2 Binds the Stress Sensor Mid2 and Functions in Polarized Cell Responses

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The AP-2 complex is a heterotetrameric endocytic cargo-binding adaptor that facilitates uptake of membrane proteins during mammalian clathrin-mediated endocytosis. While budding yeast has clear homologues of all four AP-2 subunits which form a complex and localize to endocytic sites in vivo, the function of yeast AP-2 has remained enigmatic. Here, we demonstrate that AP-2 is required for hyphal growth in Candida albicans and polarized cell responses in Saccharomyces cerevisiae. Deletion of APM4, the cargo-binding mu subunit of AP-2, causes defects in pseudohyphal growth, generation of a mating projection and the cell wall damage response. In an apm4 null mutant, the cell wall stress sensor Mid2 is unable to relocalize to the tip of a mating projection following pheromone addition, or to the mother bud neck in response to cell wall damage. A direct binding interaction between Mid2 and the mu homology domain of Apm4 further supports a model in which AP-2 binds Mid2 to facilitate its internalization and relocalization in response to specific signals. Thus, Mid2 is the first cargo for AP-2 identified in yeast. We propose that endocytic recycling of Mid2 and other components is required for polarized cell responses ensuring cell wall deposition and is tightly monitored during cell growth.

AP-2 complex in Candida albicans is required for normal hyphal growth. Budding yeast AP-2 has an important function in cell polarity responses to pheromone, nutritional status and cell wall damage. AP-2 binds to the cell wall stress receptor Mid2 and is required for its relocalization in response to pheromone and cell wall damage by calcofluor. AP-2 binds Mid2 at a site which includes a YXXΦ motif but mutation at this site is not sufficient to inhibit Mid2 relocalization.

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