SENCRstabilizes vascular endothelial cell adherens junctions through interaction with CKAP4

Abstract

SENCR is a human-specific, vascular cell-enriched long-noncoding RNA (lncRNA) that regulates vascular smooth muscle cell and endothelial cell (EC) phenotypes. The underlying mechanisms of action of SENCR in these and other cell types is unknown. Here, levels of SENCR RNA are shown to be elevated in several differentiated human EC lineages subjected to laminar shear stress. Increases in SENCR RNA are also observed in the laminar shear stress region of the adult aorta of humanized SENCR-expressing mice, but not in disturbed shear stress regions. SENCR loss-of-function studies disclose perturbations in EC membrane integrity resulting in increased EC permeability. Biotinylated RNA pull-down and mass spectrometry establish an abundant SENCR-binding protein, cytoskeletal-associated protein 4 (CKAP4); this ribonucleoprotein complex was further confirmed in an RNA immunoprecipitation experiment using an antibody to CKAP4. Structure–function studies demonstrate a noncanonical RNA-binding domain in CKAP4 that binds SENCR. Upon SENCR knockdown, increasing levels of CKAP4 protein are detected in the EC surface fraction. Furthermore, an interaction between CKAP4 and CDH5 is enhanced in SENCR-depleted EC. This heightened association appears to destabilize the CDH5/CTNND1 complex and augment CDH5 internalization, resulting in impaired adherens junctions. These findings support SENCR as a flow-responsive lncRNA that promotes EC adherens junction integrity through physical association with CKAP4, thereby stabilizing cell membrane-bound CDH5.

Long noncoding RNAs in key cellular processes involved in aortic aneurysms

“…SENCR positively regulated angiogenic processes in HUVECs [60], and was further found to be induced by laminar shear stress in human ECs [61]. Knockdown of SENCR displaced CKAP4 (Cytoskeletal-associated protein 4), which then bound CDH5 (Cadherin 5), destabilizing the CDH5/CTNND1 (Catenin delta 1) complex and perturbing EC adherens junctions [61]. SENCR has not yet been directly linked to AA disease, but the proposed mechanisms in SMCs and ECs make it an intriguing lncRNA for further exploration in disease-relevant models.…”

“…SENCR also correlated with the expression of the FIL1 (Friend Leukemia Integration virus 1) gene [59], a crucial regulator in EC function and specification. SENCR positively regulated angiogenic processes in HUVECs [60], and was further found to be induced by laminar shear stress in human ECs [61]. Knockdown of SENCR displaced CKAP4 (Cytoskeletal-associated protein 4), which then bound CDH5 (Cadherin 5), destabilizing the CDH5/CTNND1 (Catenin delta 1) complex and perturbing EC adherens junctions [61].…”

Zika virus targets the human thymic epithelium

“…We hypothesize that upregulation of PICART1 may also suppress proliferation and induce apoptosis in ZIKV-infected human TEC, as shown by other authors that this lncRNA impairing proliferation 42 and inducing apoptosis 43 in lung cancer cells. Another lncRNA, SENCR can stabilize the vascular endothelial cell adherent junctions 44 , which mediate cell adhesion and intracellular signals 45 . Accordingly, the upregulation of SENCR may be involved in regulating the enhancement of cell adhesion seen in ZIKV-infected TEC.…”

Preliminary study on the mechanism of long noncoding RNA SENCR regulating the proliferation and migration of vascular smooth muscle cells

“…Functional tests confirmed that SENCR overexpression significantly inhibited cell proliferation and migration. Besides, SENCR not only regulates the function of VSMCs but stabilizes the adhesion and connection of vascular ECs through interaction with CKAP4 (Lyu et al, 2019). Moreover, SENCR identified is involved in regulating the differentiation of ECs into pluripotent cells and controlling the angiogenic capacity of HUVEC (Boulberdaa et al, 2016).…”