RNA Biology最新文献

MicroRNAs are a class of small regulatory RNAs that mediate regulation of protein synthesis by recognizing sequence elements in mRNAs. MicroRNAs are processed through a series of steps starting from transcription and primary processing in the nucleus to precursor processing and mature function in the cytoplasm. It is also in the cytoplasm where levels of mature microRNAs can be modulated through decay mechanisms. Here, we review the recent progress in the lifetime of a microRNA at all steps required for maintaining their homoeostasis. The increasing knowledge about microRNA regulation upholds great promise as therapeutic targets.

Understanding how cells sense gases or gaseous solutes is a fundamental question in biology and is pivotal for the evolution of molecular and organismal life. In numerous organisms, gases can diffuse into cells, be transported, generated, and sensed. Controlling gases in the cellular environment is essential to prevent cellular and molecular damage due to interactions with gas-dependent free radicals. Consequently, the mechanisms governing acute gas sensing are evolutionarily conserved and have been experimentally elucidated in various organisms. However, the scientific literature on direct gas sensing is largely based on hemoprotein-based gasoreceptors (or sensors). As RNA-based G-quadruplex (G4) structures can also bind to heme, I propose that some ribozymes can act as gas-sensing riboceptors (ribonucleic acid receptors). Additionally, I present a few other ideas for non-heme metal ion- or metal cluster-based gas-sensing riboceptors. Studying riboceptors can help understand the evolutionary origins of cellular and gasocrine signaling.

The Cell Division Cycle and Apoptosis Regulator (CCAR) protein family members have recently emerged as regulators of alternative splicing and transcription, as well as having other key physiological functions. For example, mammalian CCAR2/DBC1 forms a complex with the zinc factor protein ZNF326 to integrate alternative splicing with RNA polymerase II transcriptional elongation in AT-rich regions of the DNA. Additionally, Caenorhabditis elegans CCAR-1, a homolog to mammalian CCAR2, facilitates the alternative splicing of the perlecan unc-52 gene. However, much about the CCAR family's role in alternative splicing is unknown. Here, we have examined the role of CCAR-1 in genome-wide alternative splicing in Caenorhabditis elegans and have identified new alternative splicing targets of CCAR-1 using RNA sequencing. Also, we found that CCAR-1 interacts with the spliceosome factors UAF-1 and UAF-2 using mass spectrometry, and that knockdown of ccar-1 affects alternative splicing patterns, motility, and proteostasis of UAF-1 mutant worms. Collectively, we demonstrate the role of CCAR-1 in regulating global alternative splicing in C. elegans and in conjunction with UAF-1.

Research on the origin of life investigates the transition from abiotic chemistry to the emergence of biology, with the 'RNA world hypothesis' as the leading theory. RNA's dual role in storage and catalysis suggests its importance in this narrative. The discovery of natural ribozymes emphasizes RNA's catalytic capabilities in prebiotic environments, supporting the plausibility of an RNA world and prompting exploration of precellular evolution. Collective autocatalytic sets (CASs) mark a crucial milestone in this transition, fostering complexity through autocatalysis. While modern biology emphasizes sequence-specific polymerases, remnants of CASs persist in primary metabolism highlighting their significance. Autocatalysis, driven by CASs, promotes complexity through mutually interdependent catalytic sets. Yet, the transition from ribonucleotides to complex RNA oligomers remains puzzling. Questions persist about the genesis of the first self-replicating RNA molecule, RNA's stability in prebiotic conditions, and the shift to complex molecular reproduction. This review delves into diverse facets of the RNA world's emergence, addressing critical bottlenecks and scientific advances. Integrating insights from simulation and in vitro evolution research, we illuminate the multistep biogenesis of catalytic RNA from the abiotic world. Through this exploration, we aim to elucidate the journey from the primordial soup to the dawn of life, emphasizing the interplay between chemistry and biology in understanding life's origins.

Parasitic worms (helminths) establish chronic infection within mammalian hosts by strategically regulating their host's immune responses. Deciphering the mechanisms by which host non-coding RNAs (ncRNA) co-ordinate the activation and regulation of immune cells is essential to understanding host immunity and immune-related pathology. It is also important to comprehend how pathogens secrete specific ncRNAs to manipulate gene expression of host immune cells and influence their response to infection. To investigate the contribution of both host and helminth derived ncRNAs to the activation and/or regulation of innate immune responses during a parasite infection, we examined ncRNA expression in the peritoneal macrophages from mice infected with Fasciola hepatica. We discovered the presence of several parasitic-derived miRNAs within host macrophages at 6 hrs and 18 hrs post infection. Target prediction analysis showed that these Fasciola miRNAs regulate host genes associated with the activation of host pro-inflammatory macrophages. Concomitantly, there was a distinct shift in host ncRNA expression, which was significant at 5 days post-infection. Prediction analysis suggested that these host ncRNAs target a different cohort of host genes compared to the parasite miRNAs, although the functional outcome was predicted to be similar i.e. reduced pro-inflammatory response and the promotion of a reparative/tolerant phenotype. Taken together, these observations uncover the interplay between host and parasitic ncRNAs and reveal a complementary regulation of the immune response that allows the parasite to evade immune detection and promote tissue repair for the host. These findings will provide a new understanding of the molecular interaction between parasites and host.

Although long noncoding RNAs (lncRNAs) constitute the majority of the human transcriptome, the functional roles of most remain elusive. While protein-coding genes in macrophage biology have been extensively studied, the contribution of lncRNAs in this context is poorly understood. Given the vast number of lncRNAs (>20,000), identifying candidates for functional characterization poses a significant challenge. Here, we present two complementary approaches to pinpoint and investigate lncRNAs involved in monocyte-to-macrophage differentiation: RNA-seq for functional inference and a high-throughput functional screen. These strategies enabled us to identify four lncRNA regulators of monocyte differentiation: lincRNA-JADE1, lincRNA-ANXA3, GATA2-AS1, and PPP2R5C-AS1. Preliminary insights suggest these lncRNAs may act in cis through neighbouring protein-coding genes, although their precise mechanisms remain to be elucidated. We further discuss the strengths and weaknesses of these methodologies, along with validation pipelines crucial for establishing lncRNA functionality.

Extracellular vesicles and nanoparticles (EVPs) are now recognized as a novel form of cell-cell communication. All cells release a wide array of heterogeneous EVPs with distinct protein, lipid, and RNA content, dependent on the pathophysiological state of the donor cell. The overall cargo content in EVPs is not equivalent to cellular levels, implying a regulated pathway for selection and export. In cancer, release and uptake of EVPs within the tumour microenvironment can influence growth, proliferation, invasiveness, and immune evasion. Secreted EVPs can also have distant, systemic effects that can promote metastasis. Here, we review current knowledge of EVP biogenesis and cargo selection with a focus on the role that extracellular RNA plays in oncogenesis and metastasis. Almost all subtypes of RNA have been identified in EVPs, with miRNAs being the best characterized. We review the roles of specific miRNAs that have been detected in EVPs and that play a role in oncogenesis and metastasis.

Argonaute proteins (Agos) represent a highly conserved family of proteins prevalent in all domains of life and have been implicated in various biological processes. Based on the domain architecture, Agos can be divided into long Agos and short Agos. While long Agos have been extensively studied over the past two decades, short Agos, found exclusively in prokaryotes, have recently gained attention for their roles in prokaryotic immune defence against mobile genetic elements, such as plasmids and phages. Notable functional and structural studies provide invaluable insights into the underlying molecular mechanisms of representative short Ago systems. Despite the diverse domain arrangements, short Agos generally form heterodimeric complexes with their associated effector proteins, activating the effector's enzymatic activities upon target detection. The activation of effector proteins in the short Ago systems leads to bacterial cell death, a mechanism of sacrificing individuals to protect the community.

General RNA chaperones are RNA-binding proteins (RBPs) that interact transiently and non-specifically with RNA substrates and assist in their folding into their native state. In bacteria, these chaperones impact both coding and non-coding RNAs and are particularly important for large, structured RNAs which are prone to becoming kinetically trapped in misfolded states. Currently, due to the limited number of well-characterized examples and the lack of a consensus structural or sequence motif, it is difficult to identify general RNA chaperones in bacteria. Here, we adapted a previously published in vivo RNA regional accessibility probing assay to screen genome wide for intracellular factors in E. coli affecting RNA folding, among which we aimed to uncover novel RNA chaperones. Through this method, we identified eight proteins whose deletion gives changes in regional accessibility within the exogenously expressed Tetrahymena group I intron ribozyme. Furthermore, we purified and measured in vitro properties of two of these proteins, YagL and PepA, which were especially attractive as general chaperone candidates. We showed that both proteins bind RNA and that YagL accelerates native refolding of the ribozyme from a long-lived misfolded state. Further dissection of YagL showed that a putative helix-turn-helix (HTH) domain is responsible for most of its RNA-binding activity, but only the full protein shows chaperone activity. Altogether, this work expands the current repertoire of known general RNA chaperones in bacteria.

Although Argonaute (AGO) proteins have been the focus of microRNA (miRNA) studies, we observed AGO-free mature miRNAs directly interacting with RNA-binding proteins, implying the sophisticated nature of fine-tuning gene regulation by miRNAs. To investigate microRNA-binding proteins (miRBPs) globally, we analyzed PAR-CLIP data sets to identify RBP quaking (QKI) as a novel miRBP for let-7b. Potential existence of AGO-free miRNAs were further verified by measuring miRNA levels in genetically engineered AGO-depleted human and mouse cells. We have shown that QKI regulates miRNA-mediated gene silencing at multiple steps, and collectively serves as an auxiliary factor empowering AGO2/let-7b-mediated gene silencing. Depletion of QKI decreases interaction of AGO2 with let-7b and target mRNA, consequently controlling target mRNA decay. This finding indicates that QKI is a complementary factor in miRNA-mediated mRNA decay. QKI, however, also suppresses the dissociation of let-7b from AGO2, and slows the assembly of AGO2/miRNA/target mRNA complexes at the single-molecule level. We also revealed that QKI overexpression suppresses cMYC expression at post-transcriptional level, and decreases proliferation and migration of HeLa cells, demonstrating that QKI is a tumour suppressor gene by in part augmenting let-7b activity. Our data show that QKI is a new type of RBP implicated in the versatile regulation of miRNA-mediated gene silencing.