Cell adhesion molecule interaction with Piezo1 channels is a mechanism for sub cellular regulation of mechanical sensitivity

Abstract

The discovery of Piezo1 channels as force sensors with roles in the endothelial response to fluid flow has appeared contradictory to earlier work suggesting mediation by a triad of cell adhesion molecules (CD31 and VE-cadherin) and vascular endothelial growth factor receptor 2 (VEGFR2). Here we propose an explanation. Stimulated emission depletion microscopy revealed physical proximity between Piezo1 and CD31 primarily at cell junctions. Förster resonance energy transfer measured by fluorescence lifetime imaging showed that the proteins approached to less than 10 nm. Substitution of a tyrosine residue at the distal Cterminus of CD31 prevented the interaction, suggesting intracellular association. The extracellular N-terminus also interacted, but exclusively at cell junctions. There was proximity between Piezo1 and VE-cadherin but not VEGFR2. Interaction with VE-cadherin was flowdependent, consistent with additional recruitment after flow-sensing. CD31 suppressed mechanical sensitivity of Piezo1 channels and interacted with N-terminal Piezo1 propeller arms implicated in force sensing. The data suggest partnership between Piezo1 and adhesion molecules for sub cellular tuning of force response.

Modified N-linked glycosylation status predicts trafficking defective human Piezo1 channel mutations

“…10) 62 . The glycans may also facilitate interactions with binding partners such as PECAM1 63 or E-cadherin 64 , or with specific lipids such as glycolipids 65 .…”

Mechanosensing by Piezo1 and its implications for physiology and various pathologies

“…As explained above, Piezo1 contributes to endothelial responses to laminar flow and controls the activation of atheroprotective signalling pathways by mediating the activation of eNOS. A recent study revealed the interconnectivity between PECAM‐1/VE‐cadherin/VEGFR2 and Piezo1 (Chuntharpursat‐Bon et al ., 2019). This study elegantly demonstrated that Piezo‐1 interacts with VE‐cadherin and PECAM‐1, but not VEGFR2 at cell–cell adhesion sites in a flow‐dependent manner, and that the interaction of Piezo1 with PECAM‐1 reduces the force sensitivity of Piezo1, thereby limiting overactivation of the channel (Chuntharpursat‐Bon et al ., 2019).…”

Early events in endothelial flow sensing

“…BKRB2 physically associates with and was proposed to co-signal with PECAM-1 141 . A bioRxiv preprint also reported that PECAM-1 interacts with Piezo1 to modulate Piezo1-dependent ionic currents 154 . Plexin D1, a semaphorin receptor previously implicated in axon guidance is also reportedly required for endothelial flow responses 155 .…”