Figure 2.
Sequence elements and mechanisms that regulate subcellular localization of lncRNAs. Sequence features can promote the nuclear retention or cytoplasmic enrichment of lncRNAs. Examples of nuclear retention elements are indicated by asterisks and include motifs repurposed from transposable elements, known as RIDLs, a pentamer motif in BORG, and a highly structured repeat in FIRRE, which is bound by heterogeneous nuclear ribonucleoprotein U, facilitating chromatin interaction. Loss of the pentamer motif in BORG leads to cytoplasmic export, while the nuclear retention element in XIST sequesters cytoplasmic RNAs to the nucleus. GC-rich RIDLs are associated with lncRNA cytoplasmic enrichment. Inefficient splicing may promote nuclear retention, while inefficiently spliced transcripts may use NXF1 for cytoplasmic export. RNA Pol II pausing is associated with cytoplasmic export of lncRNAs with poor splice site conservation. While m6A modification is a fast-track cytoplasmic export signal in mRNAs, it is unclear how it acts on lncRNAs. circRNAs that are >800 nt are efficiently exported to the cytoplasm through UAP56, whereas shorter ones (<800 nt) are exported through URH49. Questions remain about targeting of lncRNAs to distinct organelles or domains, such as shuttling between the nucleus and mitochondria; RBPs may play a role. The binding of HuR to RMRP in the nucleus facilitates export via CRM1, and association with GSRF influences mitochondrial localization. Stem loop structures in RNAs may facilitate mitochondrial import via PNPASE. lncRNAs associated with ribosomes have longer 5′ UTRs and are deplete of repetitive elements. Asterisks indicate nuclear retention elements. RNAs and structures are not drawn to scale and are depicted as they are for artistic purposes.