The role of Vangl2-VRK2 signaling axis in the regulation of ER morphology

Abstract

Vangl2 is a four-pass transmembrane protein that functions as a core component of Planar Cell Polarity (PCP) signaling. The PCP signaling governs a variety of polarized cell behaviors including collective cell movements and cytoskeleton remodeling, loss of which leads to severe diseases such as neural tube defects in human. However, the downstream evens and how planar polarity is achieved remain poorly understood despite its significance in development and disease. Here, using BioID proximity labeling approach, an endoplasmic reticulum (ER) membrane localized kinase VRK2 was identified to be a novel binding partner of Vangl2. More interestingly, VRK2 was found to be negatively regulated by Vangl2. Further investigations showed that Vangl2 strongly bound with VRK2 on the ER membrane and recruited an ER localized E3 ligase ZNRF4 to promote the ubiquitination of VRK2, which was subsequently retrotranslocated into cytosol through VCP/Npl4 complex and degraded by proteasome.

In addition, VRK2 was found to play a pivotal role in ER morphology regulation. Loss of VRK2 significantly increased the ER sheets ratio in cells, while overexpression resulted in long unbranched tubular ER generation. Strikingly, we found VRK2 bound with microtubule (MT) through C terminal positive charged region and tethered MT to ER membrane, whereby VRK2 modulated ER morphology within cells. Consistent with previous results, loss of Vangl2 led to increased ER tubule ratio, suggesting Vangl regulated ER morphology through negative regulation of VRK2. We also found that loss of VRK2 led to enlarged brain ventricles in mouse. Considering that vrk2 is a strong risk gene for schizophrenia, our findings suggest a potential novel function of Vangl2 in regulating ER morphology and neural development through a PCP-independent mechanism.