Cytoplasmic sequestration of p53 by lncRNA-CIRPILalleviates myocardial ischemia/reperfusion injury

Abstract

Myocardial ischemia/reperfusion (MI/R) injury is a pathological process that seriously affects the health of patients with coronary artery disease. Long non-coding RNAs (lncRNAs) represents a new class of regulators of diverse biological processes and disease conditions, the study aims to discover the pivotal lncRNA in MI/R injury. The microarray screening identifies a down-regulated heart-enriched lncRNA-CIRPIL (Cardiac ischemia reperfusion associated p53 interacting lncRNA, lncCIRPIL) from the hearts of I/R mice. LncCIRPIL inhibits apoptosis of cultured cardiomyocytes exposed to anoxia/reoxygenation (A/R). Cardiac-specific transgenic overexpression of lncCIRPIL alleviates I/R injury in mice, while knockout of lncCIRPIL exacerbates cardiac I/R injury. LncCIRPIL locates in the cytoplasm and physically interacts with p53, which leads to the cytoplasmic sequestration and the acceleration of ubiquitin-mediated degradation of p53 triggered by E3 ligases CHIP, COP1 and MDM2. p53 overexpression abrogates the protective effects of lncCIRPIL. Notably, the human fragment of conserved lncCIRPIL mimics the protective effects of the full-length lncCIRPIL on cultured human AC16 cells. Collectively, lncCIRPIL exerts its cardioprotective action via sequestering p53 in the cytoplasm and facilitating its ubiquitin-mediated degradation. The study highlights a unique mechanism in p53 signal pathway and broadens our understanding of the molecular mechanisms of MI/R injury.

Crosstalk between ubiquitin ligases and ncRNAs drives cardiovascular disease progression

“…Collectively, lncRNA-CIRPIL, lncRNA Fendrr and LINC01588 were shown to be downregulated in myocardial I/R mice or rats and to function as negative mediators of myocardial I/R-induced cardiomyocyte apoptosis by enhancing E3 ubiquitin ligases (COP1, CHIP, MDM2 and WWP2) in vivo . First, lncRNA-CIRPIL interacts with p53 and sequesters it in the cytoplasm, directly accelerating the ubiquitin-regulated degradation of p53 by upregulating the expression of E3 ubiquitin ligases COP1, CHIP and MDM2, thereby attenuating myocardial A/R-induced apoptosis and injury ( 41 ). Similar to lncRNA-CIRPIL, lncRNA Fendrr suppresses myocardial H/R-induced apoptosis by facilitating the ubiquitination degradation of p53 via COP1 ( 42 ).…”

“…Moreover, LNC01588 can make direct contact with the HNRNPL protein and upregulate the E3 ubiquitin ligase WWP2, which then reduces the levels of downstream SEPT4, thereby ameliorating myocardial oxidative stress and MI during myocardial I/R damage ( 43 ). On the other hand, inhibition of p53 ubiquitination degradation and inhibition of WWP2 attenuate the protective effects of lncCIRPIL and LINC01588 ( 41 , 43 ). Conversely, the ZFP36L2- lncRNA PVT1-miR-21-5p-MARCH5 axis positively affects the fission and fusion of mitochondria and cardiomyocyte apoptosis following myocardial I/R.…”

“…On the first level, ncRNAs are involved in the pathological processes of CVDs and function as potential therapeutic targets by directly regulating E2/E3/deubiquitinating enzyme levels and affecting downstream protein expression ( Table 2 ). Various ncRNAs exert cardioprotective effects by inhibiting downstream proteins of ubiquitination degradation (miR322, miR-322/503, miR-378a-3p, miR-454, miR-129-5p) or promoting ubiquitination degradation (lncCIRPIL, LNC01588) ( 36 – 38 , 41 , 43 , 67 , 68 ). For example, miR322, miR-322/503, miR-378a-3p, lncCIRPIL, and LNC01588 were shown to exert anti-apoptotic effects to alleviate myocardial I/R progression by inhibiting downstream proteins of FBXW7/Smurf2/TRIM55 ubiquitination or promoting ubiquitination degradation of p53/SEP4 ( 36 – 38 , 41 , 43 ).…”

“…Various ncRNAs exert cardioprotective effects by inhibiting downstream proteins of ubiquitination degradation (miR322, miR-322/503, miR-378a-3p, miR-454, miR-129-5p) or promoting ubiquitination degradation (lncCIRPIL, LNC01588) ( 36 – 38 , 41 , 43 , 67 , 68 ). For example, miR322, miR-322/503, miR-378a-3p, lncCIRPIL, and LNC01588 were shown to exert anti-apoptotic effects to alleviate myocardial I/R progression by inhibiting downstream proteins of FBXW7/Smurf2/TRIM55 ubiquitination or promoting ubiquitination degradation of p53/SEP4 ( 36 – 38 , 41 , 43 ). MiR322/503 (homolog of human miR-424) reduces myocardial I/R-induced apoptosis and infarct size via the miR-424(322)/503/FBXW7/N1-ICD/HIF-1α and miR-424(322)/503/Smurf2/EZH2 axes ( 36 , 37 ).…”

Unveiling the Hidden Regulators: The Impact of lncRNAs on Zoonoses

“…Conversely, in the cytoplasm, lncRNAs are primarily influenced by post-transcriptional events, including maintaining the stability of mRNA, sponging microRNAs to influence gene silencing, and regulating the integrity and activity of protein complexes [ 20 , 21 ]. Additionally, certain cytoplasmic lncRNAs can indirectly impact transcription by interacting with transcription factors [ 22 ]. Besides conventional regulatory mechanisms, recent studies have identified open reading frames (ORFs) within some cytoplasmic lncRNAs, suggesting they can encode functional peptides, and perform significant roles in various pathological processes [ 23 , 24 , 25 ].…”