RNAs as Regulators of Cellular Matchmaking

Abstract

RNA molecules are increasingly being identified as facilitating or impeding the interaction of proteins and nucleic acids, serving as so-called scaffolds or decoys. Long non-coding RNAs have been commonly implicated in such roles, particularly in the regulation of nuclear processes including chromosome topology, regulation of chromatin state and gene transcription, and assembly of nuclear biomolecular condensates such as paraspeckles. Recently, an increased awareness of cytoplasmic RNA scaffolds and decoys has begun to emerge, including the identification of non-coding regions of mRNAs that can also function in a scaffold-like manner to regulate interactions of nascently translated proteins. Collectively, cytoplasmic RNA scaffolds and decoys are now implicated in processes such as mRNA translation, decay, protein localization, protein degradation and assembly of cytoplasmic biomolecular condensates such as P-bodies. Here, we review examples of RNA scaffolds and decoys in both the nucleus and cytoplasm, illustrating common themes, the suitability of RNA to such roles, and future challenges in identifying and better understanding RNA scaffolding and decoy functions.

Keywords: 3′UTR; RNA decoys; RNA scaffolds; lncRNA; mRNA; nascent protein interactions.

FIGURE 1

Examples of nuclear RNA scaffolds and decoys. Scaffold and decoy RNAs are depicted in pink. (A) Telomere extension: the TR lncRNA scaffolds and provides the telomeric repeat template for the Telomerase complex that consists of the reverse transcriptase protein (TERT) along with other accessory proteins that function in telomere extension. (B) Chromatin regulation: Xist lncRNA establishes X chromosome inactivation by (1) hnRNP K initiated recruitment of; non-canonical PRC1 complex (Ub ligase) (2), whose activities recruit (3) canonical PRC1 and PRC2 (methyltransferases). HOTAIR recruits PRC2 and LSD1 (demethylase) to modify chromatin at numerous gene loci, including the HOXD locus. (C) Chromosome topology: (i) Firre lncRNA expressed from the active X chromosome, establishes chromosome territories by bringing together loci across multiple different chromosomes with the help of interaction with hnRNP U. (ii) Xist lncRNA can interact with the Lamin B receptor, resulting in recruitment of the inactivated X chromosome (“Barr body”) to the nuclear lamina. (D) Nuclear bodies: NEAT1–2 lncRNA acts as an RNA scaffold driving the assembly of nuclear paraspeckles via its interaction with NONO, SFPQ and several other proteins. NEAT1–2 facilitates NONO-Microprocessor interactions to aid in pri-miRNA processing. Paraspeckles also sequester Inosine-modified RNAs, preventing their export. (E) Toxic RNA decoy: CUG repeat expansions in the 3′UTR of DMPK sequester Muscleblind-like (MBNL) proteins, thus impairing alternative splicing.

FIGURE 2

7SL – a paradigm of cytoplasmic RNA scaffolding. (1) Translation of proteins with N-terminal signal peptides (green) are bound by SRP complex, scaffolded by 7SL. (2) Signal peptide binding induces SRP conformational change and tighter binding, thus block ribosomal A-site and stalling translation elongation. (3) SRP interaction with SRP receptor positions nascent peptide for entry into ER translocon. (4) Dissociation of SRP relieves elongation stall, and nascent peptide extends into and folds within ER lumen.

FIGURE 3

Examples of cytoplasmic RNA scaffolds and decoys. Scaffold and decoy RNAs are depicted in pink (A) mRNA translation: lncRNA-p21 partially base pairs with target mRNAs leading to the recruitment of translation repression factors like RCK and FMRP, thus inhibiting mRNA translation. (B) mRNA decay: 1/2sbsRNAs base pair with target mRNAs; the resulting dsRNA recruits Staufen, leading to staufen-mediated mRNA decay. (C) miRNA sequestration: various lncRNAs (linear and circular) in multiple species, regulated in a tissue, developmental or environmentally sensitive manner, can base-pair with and sequester miRNAs, preventing their regulation of mRNA translation or decay. (D) Protein degradation: HOTAIR lncRNA binds to two ubiquitin ligases and their substrates causing their ubiquitination and degradation.

FIGURE 4

mRNAs as cytoplasmic RNA scaffolds. (A) Protein localization: (1) The CD47-LU mRNA 3′UTR recruits HuR and SET. (2) Within TIS11B-ER membrane compartments (TIS granules), nascently translated CD47’s interaction with SET is facilitated. (3) Recruitment of RAC1 by SET results in subsequent translocation of CD47 to the plasma membrane. (B) mRNP granule assembly: (1) The RPS28B 3′UTR is presumed to recruit Edc3 prior to its subsequent interaction, (2) with either nascently or newly translated Rps28. (3) Since translating mRNAs are excluded from mRNP granules, ribosome run-off is likely required for an RPS28B-Edc3-Rps28 RNP complex to help nucleate yeast P-body assembly.