Li, F.-F. | Search bioRxiv

bioRxiv2022

PP2A forestalls mitophagy by dephosphorylating Parkin and ubiquitin

Mitophagy is a selective autophagic process that removes damaged mitochondria. PINK1-Parkin axis is primarily responsible for initiating mitophagy via feedforward mechanism, in which PINK1 phosphorylates ubiquitin and Parkin, and Parkin gains E3 ligase activity at the mitochondrial outer membrane. However, the phosphatase of pParkin is unknown, and the braking mechanism of mitophagy is incomplete. Here we report that protein phosphatase 2A (PP2A) catalyzes the dephosphorylation of Parkin and ubiquitin, with C, A, and B55, the catalytic scaffolding and regulatory subunits, respectively. Up- or down-regulation of PP2A protein level in cells by over-expression or transfection of specific siRNA decreases or increases Parkin and ubiquitin phosphorylation levels, respectively. Consequently, PP2A phosphatase activity negatively modulates mitochondrial translocation of Parkin and forestalls mitophagy. Our finding thus places PP2A, an enzyme already known for its involvement in the pathogenesis of neurodegenerative diseases, further intertwined with the PINK1-Parkin signaling pathway.

biochemistry↗

bioRxiv2020

Lnc-ECAL-1 controls cerebrovascular homeostasis by targeting endothelium-specific tight junction protein Cldn5b

Cerebrovascular disorder-induced brain blood flow interruption or intracranial hemorrhage pose a great threaten to health. Emerging roles of long-noncoding RNAs (lncRNAs) in diagnosis and treatment of cardiovascular diseases have been recognized. However, whether and how lncRNAs modulate vascular homeostasis, especially network formation remain largely unknown. Here, we identified ECAL-1, a long non-coding RNA, as an important determinant for cerebrovascular homeostasis. Using the morpholino- and CRISPR /Cas9-based genetic modifications in combination with in vivo confocal imaging in zebrafish, we claimed that inactivation of ECAL-1 induced the apparent distortion of cerebral vascular pattern accompanied by intracranial hemorrhage. These cerebrovascular abnormalities were associated with decreased proliferation and anomalous interconnection of endothelial cells. Importantly, overexpression of Cldn5b, an endothelial cell-specific tight junction protein-encoding gene, could partially rescued the phenotype induced by ECAL-1 deficiency. Furthermore, bioinformatic analysis and experimental validation revealed that ECAL-1 sponged miR-23a, which targeted Cldn5b 3UTR and modulated Cldn5b expression, to maintain cerebrovascular pattern formation and integrity. Our results presented here revealed that ECAL-1 specifically controls cerebrovascular network formation and integrity through targeting miR-23a-Cldn5b axis. These findings provide a new regulation modality for cerebrovascular patterning and the potential neurovascular disorders, and ECAL-1-miR-23a axis represents as an attractive therapeutic target for cerebrovascular diseases.

developmental biology↗