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Cell-cell mechanotransduction regulates tissue development and homeostasis. α-catenin, the core component of adherens junctions, functions as a tension sensor and transducer by recruiting vinculin and transducing signals that influence cell behaviors. α-catenin/vinculin complex-mediated mechanotransduction regulates multiple pathways, such as Hippo pathway. However, their associations with the α-catenin-based tension sensors at cell junctions are still not fully addressed. Here, we uncovered the TRIP6/LATS1 complex co-localizes with α-catenin/vinculin at both bicellular junctions (BCJs) and tricellular junctions (TCJs). The localization of TRIP6/LATS1 complex to both TCJs and BCJs requires ROCK1 and α-catenin. Treatment by cytochalasin B, Y-27632 and blebbistatin all impaired the BCJ and TCJ junctional localization of TRIP6/LATS1, indicating that the junctional localization of TRIP6/LATS1 is mechanosensitive. The α-catenin/vinculin/TRIP6/LATS1 complex strongly localized to TCJs and exhibited a discontinuous button-like pattern on BCJs. Additionally, we developed and validated an α-catenin/vinculin BiFC-based mechanosensor that co-localizes with TRIP6/LATS1 at BCJs and TCJs. The mechanosensor exhibited a discontinuous distribution and motile signals at BCJs. Overall, our study revealed that TRIP6 and LATS1 are novel compositions of the tension sensor, together with the core complex of α-catenin/vinculin, at both the BCJs and TCJs.

Desmosomes play a crucial role in maintaining tissue barrier integrity, particularly in mechanically stressed tissues. The assembly of desmosomes is regulated by the cytoskeleton and its regulators, and desmosomes also function as a central hub for regulating F-actin. However, the specific mechanisms underlying the crosstalk between desmosomes and F-actin remain unclear. Here, we identified that ARHGAP32, a Rho GTPase-activating protein, is located in desmosomes through its interaction with desmoplakin (DSP) via its GAB2-interacting domain (GAB2-ID).We confirmed that ARHGAP32 is required for desmosomal organization, maturation and length regulation. Notably, loss of ARHGAP32 increased formation of F-actin stress fibers and phosphorylation of the regulatory myosin light chain Myl9 at T18/S19. Inhibition of ROCK activity in ARHGAP32-knockout (KO) cells effectively restored desmosomal organization and the integrity of epithelial cell sheets. Moreover, loss of DSP impaired desmosomal ARHGAP32 location and led to decreased actomyosin contractility. ARHGAP32 with a deletion of the GAB2-ID domain showed enhanced association with RhoA in the cytosol and failed to rescue the desmosomal organization in ARHGAP32-KO cells. Collectively, our study unveils that ARHGAP32 associates with and regulates desmosomes by interacting with DSP. This interaction potentially facilitates the crosstalk between desmosomes and F-actin. [ABSTRACT FROM AUTHOR]