Electrostatic plasma membrane targeting contributes to Dig function in cell polarity and tumorigenesis

Discs large (Dig) is an essential polarity protein and a tumor suppressor originally characterized in Drosophila but also well conserved in vertebrates. Like the majority of polarity proteins, plasma membrane (PM)/cortical localization of Dig is required for its function in polarity and tumorigenesis, but the exact mechanisms targeting Dig to the PM remain to be fully elucidated. Here, we show that, similar to recently discovered polybasic polarity proteins such as Lgl and aPKC, Dig also contains a positively charged polybasic domain that electrostatically binds the PM phosphoinositides PI4P and PI(4,5)P-2. Electrostatic targeting by the polybasic domain contributes significantly to the PM localization of Dig in follicular and early embryonic epithelial cells, and is crucial for Dig to regulate both polarity and tumorigenesis. The electrostatic PM targeting of Dig is controlled by a potential phosphorylation-dependent allosteric regulation of its polybasic domain, and is specifically enhanced by the interactions between Dig and another basolateral polarity protein and tumor suppressor, Scrib. Our studies highlight an increasingly significant role of electrostatic PM targeting of polarity proteins in regulating cell polarity.

Automated summary

Dig, an essential polarity protein and tumor suppressor, contains a positively charged polybasic domain that binds to phosphoinositides on the plasma membrane, contributing significantly to its localization and function in polarity and tumorigenesis. This electrostatic targeting of Dig is controlled by potential phosphorylation-dependent regulation and interactions with other polarity proteins, highlighting the importance of electrostatic PM targeting in regulating cell polarity.