Beta]‐arrestin 1 mediates angiotensin II induced ubiquitination and down‐regulation of TRPV4

Abstract

β‐arrestins were originally discovered to desensitize activated G protein‐coupled receptors (GPCRs), also known as seven transmembrane receptor (7TMRs). It was subsequently found that β‐arrestins also mediate 7TMR internalization by bringing the activated receptors to clathrin‐coated pits. More recently, it has been discovered that β‐arrestins can also interact with and regulate ion channels and transporters. Using a proteomic approach, we identified TRPV4 as an interacting partner of β‐arrestin 1 after stimulation of cells with angiotensin II. Here we demonstrate that β‐arrestin 1 is recruited to TRPV4 upon angiotensin II stimulation in HEK‐293 cells and vascular smooth muscle cells. Surprisingly, angiotensin II stimulation leads to ubiquitination of TRPV4 which is abolished by β‐arrestin 1 siRNA. β‐arrestin 1 shows constitutive interaction with AIP4, a known ubiquitin E3 ligase for TRPV4, which is further increased upon angiotensin stimulation. Moreover, the interaction of TRPV4 and AIP4 is also significantly reduced by β‐arrestin 1 siRNA. These findings suggest that β‐arrestin 1 serves as an adaptor for AIP4 and thereby facilitates TRPV4 ubiquitination and down‐regulation. Taken together with the previous reports of analogous function of β‐arrestins for 7TMRs, this study suggests a novel role of β‐arrestins as a general adaptor for ubiquitin E3 ligases.