Journal Article

A macrophage-specific lncRNA regulates apoptosis and atherosclerosis by tethering HuR in the nucleus

Papotti, Bianca, Tesmenitsky, Yevgenia, Haemmig, Stefan, Chen, Alex F., Marto, Jarrod A., Feinberg, Mark W., Mendes, Shanelle, Simion, Viorel, Ronda, Nicoletta, Zhou, Haoyang, Pérez-Cremades, Daniel, Pierce, Jacob B., Lee, James F.

2020

Overview

Long non-coding RNAs (lncRNAs) are emerging regulators of pathophysiological processes including atherosclerosis. Using RNA-seq profiling of the intima of lesions, here we identify a macrophage-specific lncRNA MAARS (Macrophage-Associated Atherosclerosis lncRNA Sequence). Aortic intima expression of MAARS increases by 270-fold with atherosclerotic progression and decreases with regression by 60%. MAARS knockdown reduces atherosclerotic lesion formation by 52% in LDLR −/− mice, largely independent of effects on lipid profile and inflammation, but rather by decreasing macrophage apoptosis and increasing efferocytosis in the vessel wall. MAARS interacts with HuR/ELAVL1, an RNA-binding protein and important regulator of apoptosis. Overexpression and knockdown studies verified MAARS as a critical regulator of macrophage apoptosis and efferocytosis in vitro, in an HuR-dependent manner. Mechanistically, MAARS knockdown alters HuR cytosolic shuttling, regulating HuR targets such as p53, p27, Caspase-9, and BCL2. These findings establish a mechanism by which a macrophage-specific lncRNA interacting with HuR regulates apoptosis, with implications for a broad range of vascular disease states. Long non coding RNA molecules have been implicated in the immunopathology of a range of inflammatory pathologies. Here the authors show lncRNA MAARS regulates apoptosis via interaction with HuR in the context of atherosclerosis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/89 / 38 / 38/71 / 38/90 / 42 / 59 / 631/80/304 / 631/80/82 / 692/4019 / 692/4019/592 / Animals / Aorta / Apoptosis / Arteriosclerosis / Atherosclerosis / Atherosclerosis - genetics / Atherosclerosis - metabolism / Atherosclerosis - physiopathology / Caspase-9 / Cell Nucleus - genetics / Cell Nucleus - metabolism / ELAV-Like Protein 1 - genetics / ELAV-Like Protein 1 - metabolism / Humanities and Social Sciences / Humans / HuR protein / Inflammation / Lesions / Lipids / Macrophages / Macrophages - cytology / Macrophages - metabolism / Mice / Mice, Inbred C57BL / multidisciplinary / Non-coding RNA / p53 Protein / Protein Transport / Regulators / Ribonucleic acid / RNA / RNA, Long Noncoding - genetics / RNA, Long Noncoding - metabolism / RNA-binding protein / Science / Science (multidisciplinary) / Species Specificity / Tethering / Vascular diseases