Emerging Roles of Long Noncoding RNAs in the Cytoplasmic Milieu

Abstract

While the important functions of long noncoding RNAs (lncRNAs) in nuclear organization are well documented, their orchestrating and architectural roles in the cytoplasmic environment have long been underestimated. However, recently developed fractionation and proximity labelling approaches have shown that a considerable proportion of cellular lncRNAs is exported into the cytoplasm and associates nonrandomly with proteins in the cytosol and organelles. The functions of these lncRNAs range from the control of translation and mitochondrial metabolism to the anchoring of cellular components on the cytoskeleton and regulation of protein degradation at the proteasome. In the present review, we provide an overview of the functions of lncRNAs in cytoplasmic structures and machineries und discuss their emerging roles in the coordination of the dense intracellular milieu. It is becoming apparent that further research into the functions of these lncRNAs will lead to an improved understanding of the spatiotemporal organization of cytoplasmic processes during homeostasis and disease.

Keywords: Long noncoding RNA; cytoplasm; cytosol; lncRNA; organelles; phase-separation; translation.

Figure 1

Exemplary illustration of lncRNAs in cytoplasmic structures and machineries. Many lncRNAs are exported from the nucleus and subsequently shuttled to specific cytoplasmic locations. Representative examples of lncRNAs are shown. Ribosome assembly and translation, for instance, is regulated by lncRNAs such as ZFAS1 or AS-UCHL1. At the endoplasmic reticulum (ER), the 7SL RNA scaffolds the signal recognition particle (SRP) to promote co-translational protein translocation. Several lncRNAs, including RMRP and lncCytB regulate mitochondrial translation and energy balance. LncRNA HOTTIP is packaged into extracellular vesicles (EVs) and was suggested as a liquid biopsy marker in colorectal cancer. LINK-A, LASSIE and lnc-CRYBG3 associate with the plasma membrane, adherence junctions and the cytoskeleton, respectively, as regulatory or architectural elements. Formation of cytosolic aggregates, including stress granules and ubiquitin foci, involves lncRNAs such as NORAD or MaIL1. Ubiquitin-dependent proteasomal degradation is regulated by several lncRNAs, including NRON. Systematic proximity labelling studies suggest further lncRNAs to be shuttled to distinct cytoplasmic destinations, including the ER and the Golgi apparatus, but remain to be functionally characterized.