α-Catenin phosphorylation is tension-sensitive and supports epithelial barrier functions via afadin.

Abstract

Zonula adherens junctions (zAJs) are spatially proximal to tight junctions (TJs), in a superstructure known as the apical junctional complex (AJC). A key component of the AJC is a circumferential ring of F-actin, but how actomyosin contractility drives AJC structure and epithelial barrier function is incompletely understood. Here, we show that a central mechanosensitive component of zAJ, α-catenin (α-cat), undergoes force-dependent phosphorylation in an unstructured linker region. This modification in turn primes the α-cat middle region for effector binding. We credential afadin, a TJ/AJ scaffold protein, as a mechanochemical binding partner of α-cat, identifying residues in α-cat required for binding. α-Cat phosphorylation and afadin binding support their co-enrichment at zAJ and barrier function. A mouse model that prevents α-cat phosphorylation is particularly detrimental to postnatal brain development, leading to hydrocephalus with junctional features similar to an afadin-binding mutant form of α-cat. These data support a model where α-cat integrates mechanical and chemical signals to progressively promote zAJ enrichment, effector recruitment, and barrier function.