Encoding activities of non-coding RNAs

Abstract

The universal expression of various non-coding RNAs (ncRNAs) is now considered the main feature of organisms' genomes. Many regions in the genome are transcribed but not annotated to encode proteins, yet contain small open reading frames (smORFs). A widely accepted opinion is that a vast majority of ncRNAs are not further translated. However, increasing evidence underlines a series of intriguing translational events from the ncRNAs, which were previously considered to lack coding potential. Recent studies also suggest that products derived from such novel translational events display important regulatory functions in many fundamental biological and pathological processes. Here we give a critical review on the potential coding capacity of ncRNAs, in particular, about what is known and unknown in this emerging area. We also discuss the possible underlying coding mechanisms of these extraordinary ncRNAs and possible roles of peptides or proteins derived from the ncRNAs in disease development and theranostics. Our review offers an extensive resource for studying the biology of ncRNAs and sheds light into the use of ncRNAs and their corresponding peptides or proteins for disease diagnosis and therapy.

Keywords: coding; ncRNAs; peptides; proteins; translation.

Figure 1

Kinds of ncRNAs-derived small peptides involved in theranostics. Some genome genes are transcribed to be ncRNAs including housekeeping ncRNAs (tRNAs, rRNAs and snRNAs) and regulatory ncRNAs. The functions of these ncRNAs are relatively clear. Regulatory ncRNAs include miRNAs, lncRNAs, circRNAs and transcripts from repeat sequences. As illustrated, by binding with ribosomes in the cytoplasm, these ncRNAs are further translated into small peptides. Circ-ZNF609 is translated and the produced small peptides function in myogenesis. These small peptides are involved in regulating muscle performance, suppressing colon cancer growth, promoting embryo cells internalization/migration, leading to FTLD/ALS and accumulation of mature miRNAs. (FTLD/ALS: frontotemporal lobar degeneration and amyotrophic lateral sclerosis; lncRNAs: long non-coding RNAs; miRNAs: microRNAs; ncRNAs: non-coding RNAs;rRNAs: ribosomal RNAs; snRNAs: small nuclear RNAs; tRNAs: transfer RNAs).

Figure 2

Toddler is an embryonic signal that promotes cell internalization and migration during the embryogenesis of zebrafish. Toddler is annotated as a lncRNA ENSDARG00000094729. It contains a 58-aa smORF and is also capped and polyadenylated, so it can be caught by ribosome and produce peptides named Toddler. The normal expression of Toddler can promote cell internalization and migration during the embryogenesis of zebrafish via the G-protein-coupled APJ/Apelin receptor. However, the overexpression or inhibition of Toddler will inhibit cell internalization and migration.

Figure 3

MLN (from LINC00948) is a skeletal muscle-specific small peptide that regulates muscle performance by modulating intracellular calcium handling. MLN shares structural and functional similarity with PLN and SLN, which inhibit SERCA, the membrane pump that controls muscle relaxation by regulating Ca²⁺ uptake into SR. (KO: knock out; MLN: myoregulin; PLN: phospholamban; ; SERCA: sarco endoplasmic reticulum Ca²⁺ -ATPase; SLN: sarcolinpin; SR: sarcoplasmic reticulum; WT: wild type). Reproduced with permission from , copyright 2015 Elsevier.

Figure 4

Working model for DWORF (from LOC100507537) function. DWORF localizes to the SR membrane, where it enhances SERCA activity by displacing the SERCA inhibitor PLN. (DWORF: dwarf open reading frame). Adapted with permission from , copyright 2016 Springer.

Figure 5

Small peptide SPAR derived from LINC00961 involved in working model of mTORC1 activation and signaling with SPAR. With the stimulation of amino acids (aa), Ragulator is released from v-ATPase and then interacts with Rags to facilitate mTORC1 recruitment. Rag proteins are mostly activated by Rheb, but can also be regulated through additional mechanisms involving the aa leucine and arginine. SPAR interacts with v-ATPase to promote and stabilize the interaction between the v-ATPase. (aa: amino acids; AKT: protein kinase B; GDP: guanosine diphosphate; GTP: guanosine triphosphate; SPAR: small regulatory polypeptide of amino acid response). Reproduced with the permission from , copyright 2016 Springer.

Figure 6

The assumed mechanism for translation initiation with special structure. (A) The classical mechanism for translation initiation. The complex composed of eIF4E, eIF4G, eIF4A, binds to the 5' cap of target RNA molecules. The poly A-binding protein (PABP) is associated with eIF4G to circularize the target mRNA molecules. Then, the eIF4F complex recruits the 43S pre-initiation complex (PIC), composed of the 40S ribosomal subunit, 30S ribosomal subunit, and the ternary complex, consisting of initiator methionine-tRNA and GTP. Next, the PIC and the components of the eIF4F complex scan through the 5'UTR in the 5' to 3' direction until encountering an AUG start codon, at which point the translation activity will be triggered by the present AUG codon. (B-C) Studies have shown that some Kozak sequences with AUG codon (B) and hairpin-structures such as (GGGGCC)n (C) can substitute the AUG codon and trigger the translation activity.

Figure 7

Schematic diagram of circRNA translation driven by m⁶A. The circRNAs here are those with m⁶A motifs. This m⁶A driven translation requires initiation factor eIF4G2 and m⁶A reader YTHDF3, and is enhanced by methyltransferase METTL3/14, inhibited by demethylase FTO. (m⁶A: N⁶-methyladenosine; YTHDF3: YTH domain family protein 3; eIF4G2: eukaryotic translation initiation factor 4 gamma 2; METTL3/14: methyltransferase-like 3/14; FTO: fat mass and obesity-associated protein). Adapted with the permission from , copyright 2017 Springer.

Figure 8

Working model for HOXB-AS3 peptide. Instead of functioning by lncRNA directly, the peptide derived from HOXB-AS3 competitively binds to the arginine residues in RGG motif of hnRNP A1 and antagonizes the hnRNP A1-mediated regulation of pyruvate kinase M (PKM) splicing by blocking the binding of the arginine residues in RGG motif of hnRNP A1 to the sequences flanking PKM exon 9, ensuring the formation of lower PKM2 and suppressing glucose metabolism reprogramming. (hnRNP: heterogeneous nuclear ribonucleoprotein; HOXB-AS3: HOXB cluster antisense RNA 3; PKM: pyruvate kinase M; RGG: Arg-Gly-Gly; TCA cycle: tricarboxylic acid cycle). Adapted with the permission from ref , copyright 2016 Elsevier.