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Nature Aug 2022Argonaute proteins use nucleic acid guides to find and bind specific DNA or RNA target sequences. Argonaute proteins have diverse biological functions and many retain...
Argonaute proteins use nucleic acid guides to find and bind specific DNA or RNA target sequences. Argonaute proteins have diverse biological functions and many retain their ancestral endoribonuclease activity, cleaving the phosphodiester bond between target nucleotides t10 and t11. In animals, the PIWI proteins-a specialized class of Argonaute proteins-use 21-35 nucleotide PIWI-interacting RNAs (piRNAs) to direct transposon silencing, protect the germline genome, and regulate gene expression during gametogenesis. The piRNA pathway is required for fertility in one or both sexes of nearly all animals. Both piRNA production and function require RNA cleavage catalysed by PIWI proteins. Spermatogenesis in mice and other placental mammals requires three distinct, developmentally regulated PIWI proteins: MIWI (PIWIL1), MILI (PIWIL2) and MIWI2 (PIWIL4). The piRNA-guided endoribonuclease activities of MIWI and MILI are essential for the production of functional sperm. piRNA-directed silencing in mice and insects also requires GTSF1, a PIWI-associated protein of unknown function. Here we report that GTSF1 potentiates the weak, intrinsic, piRNA-directed RNA cleavage activities of PIWI proteins, transforming them into efficient endoribonucleases. GTSF1 is thus an example of an auxiliary protein that potentiates the catalytic activity of an Argonaute protein.
Topics: Animals; Argonaute Proteins; Biocatalysis; Female; Intracellular Signaling Peptides and Proteins; Male; Mice; RNA Cleavage; RNA, Small Interfering
PubMed: 35772669
DOI: 10.1038/s41586-022-05009-0 -
Nature Communications Dec 2018Recognition and repression of RNA targets by Argonaute proteins guided by small RNAs is the essence of RNA interference in eukaryotes. Argonaute proteins with diverse... (Review)
Review
Recognition and repression of RNA targets by Argonaute proteins guided by small RNAs is the essence of RNA interference in eukaryotes. Argonaute proteins with diverse structures are also found in many bacterial and archaeal genomes. Recent studies revealed that, similarly to their eukaryotic counterparts, prokaryotic Argonautes (pAgos) may function in cell defense against foreign genetic elements but, in contrast, preferably act on DNA targets. Many crucial details of the pAgo action, and the roles of a plethora of pAgos with non-conventional architecture remain unknown. Here, we review available structural and biochemical data on pAgos and discuss their possible functions in host defense and other genetic processes in prokaryotic cells.
Topics: Argonaute Proteins; Catalysis; Catalytic Domain; DNA; Eukaryota; Eukaryotic Cells; Genetic Engineering; Immune System; Prokaryotic Cells; Protein Binding; Protein Domains; Protein Interaction Domains and Motifs; RNA; RNA Interference; RNA, Small Interfering
PubMed: 30514832
DOI: 10.1038/s41467-018-07449-7 -
Nature Structural & Molecular Biology Sep 2014Argonaute proteins are conserved throughout all domains of life. Recently characterized prokaryotic Argonaute proteins (pAgos) participate in host defense by DNA... (Review)
Review
Argonaute proteins are conserved throughout all domains of life. Recently characterized prokaryotic Argonaute proteins (pAgos) participate in host defense by DNA interference, whereas eukaryotic Argonaute proteins (eAgos) control a wide range of processes by RNA interference. Here we review molecular mechanisms of guide and target binding by Argonaute proteins, and describe how the conformational changes induced by target binding lead to target cleavage. On the basis of structural comparisons and phylogenetic analyses of pAgos and eAgos, we reconstruct the evolutionary journey of the Argonaute proteins through the three domains of life and discuss how different structural features of pAgos and eAgos relate to their distinct physiological roles.
Topics: Animals; Argonaute Proteins; Evolution, Molecular; Humans; Models, Molecular; Phylogeny; Protein Binding; Protein Conformation
PubMed: 25192263
DOI: 10.1038/nsmb.2879 -
International Journal of Molecular... Oct 2023The recent pandemic of SARS-CoV-2 has underscored the critical need for rapid and precise viral detection technologies. Point-of-care (POC) technologies, which offer... (Review)
Review
The recent pandemic of SARS-CoV-2 has underscored the critical need for rapid and precise viral detection technologies. Point-of-care (POC) technologies, which offer immediate and accurate testing at or near the site of patient care, have become a cornerstone of modern medicine. Prokaryotic Argonaute proteins (pAgo), proficient in recognizing target RNA or DNA with complementary sequences, have emerged as potential game-changers. pAgo present several advantages over the currently popular CRISPR/Cas systems-based POC diagnostics, including the absence of a PAM sequence requirement, the use of shorter nucleic acid molecules as guides, and a smaller protein size. This review provides a comprehensive overview of pAgo protein detection platforms and critically assesses their potential in the field of viral POC diagnostics. The objective is to catalyze further research and innovation in pAgo nucleic acid detection and diagnostics, ultimately facilitating the creation of enhanced diagnostic tools for clinic viral infections in POC settings.
Topics: Humans; Point-of-Care Systems; Argonaute Proteins; Prokaryotic Cells; Point-of-Care Testing; Nucleic Acids; CRISPR-Cas Systems
PubMed: 37834437
DOI: 10.3390/ijms241914987 -
Trends in Cell Biology Mar 2023Ribosome-associated protein quality control (RQC) is a protein surveillance mechanism that eliminates defective nascent polypeptides. The E3 ubiquitin ligase, Ltn1, is a... (Review)
Review
Ribosome-associated protein quality control (RQC) is a protein surveillance mechanism that eliminates defective nascent polypeptides. The E3 ubiquitin ligase, Ltn1, is a key regulator of RQC that targets substrates for ubiquitination. Argonaute proteins (AGOs) are central players in miRNA-mediated gene silencing and have recently been shown to also regulate RQC by facilitating Ltn1. Therefore, AGOs directly coordinate post-transcriptional gene silencing and RQC, ensuring efficient gene silencing. We summarize the principles of RQC and the functions of AGOs in miRNA-mediated gene silencing, and discuss how AGOs associate with the endoplasmic reticulum (ER) to assist Ltn1 in controlling RQC. We highlight that RQC not only eliminates defective nascent polypeptides but also removes unwanted protein products when AGOs participate.
Topics: Humans; Argonaute Proteins; Ribosomes; Ubiquitination; Ubiquitin-Protein Ligases; Saccharomyces cerevisiae Proteins; Peptides; MicroRNAs; Protein Biosynthesis
PubMed: 35981909
DOI: 10.1016/j.tcb.2022.07.007 -
Biological Chemistry Oct 2023MicroRNA (miRNA)-guided gene silencing is a key regulatory process in various organisms and linked to many human diseases. MiRNAs are processed from precursor molecules... (Review)
Review
MicroRNA (miRNA)-guided gene silencing is a key regulatory process in various organisms and linked to many human diseases. MiRNAs are processed from precursor molecules and associate with Argonaute proteins to repress the expression of complementary target mRNAs. Excellent work by numerous labs has contributed to a detailed understanding of the mechanisms of miRNA function. However, miRNA effects have mostly been analyzed and viewed as isolated events and their natural environment as part of complex RNA-protein particles (RNPs) is often neglected. RNA binding proteins (RBPs) regulate key enzymes of the miRNA processing machinery and furthermore RBPs or readers of RNA modifications may modulate miRNA activity on mRNAs. Such proteins may function similarly to miRNAs and add their own contributions to the overall expression level of a particular gene. Therefore, post-transcriptional gene regulation might be more the sum of individual regulatory events and should be viewed as part of a dynamic and complex RNP world.
Topics: Humans; RNA Interference; MicroRNAs; Gene Expression Regulation; RNA-Binding Proteins; Argonaute Proteins
PubMed: 37739934
DOI: 10.1515/hsz-2023-0203 -
Postepy Biochemii Sep 2022ARGONAUTE (AGO) proteins are integral parts of regulatory pathways under the control of small RNA (sRNA) that are fundamental for the proper functioning of eukaryotic... (Review)
Review
ARGONAUTE (AGO) proteins are integral parts of regulatory pathways under the control of small RNA (sRNA) that are fundamental for the proper functioning of eukaryotic cells. AGOs, as highly specialized platforms binding specific sRNA, coordinate gene silencing through interaction with other protein factors (forming the RNA-induced silencing complex, RISC), contributing to endonucleolytic cleavage of the target mRNA and/or influencing the translation process. The increasing number of evidence confirms the participation of AGO proteins in several other cellular processes, such as i.e.: transcription regulation, sequestration, RNA-dependent methylation of DNA, repair of DNA damages, synthesis of siRNA independent of DCL (DICER-like) proteins, or co-transcriptional regulation of MIRNA genes expression and intron splicing. Particular plant species are characterized by the presence of a different number of AGO proteins, in many cases of yet unknown regulatory and/or biological function. This review article covers the current knowledge about the functions of AGOs in cell biology and plant development.
Topics: Argonaute Proteins; Plant Development; RNA, Small Interfering; Plants; Gene Silencing; MicroRNAs; Plant Proteins; Gene Expression Regulation, Plant
PubMed: 36317991
DOI: 10.18388/pb.2021_450 -
The Journal of Biological Chemistry Jan 2024Argonaute (AGO) proteins in all three domains of life form ribonucleoprotein or deoxyribonucleoprotein complexes by loading a guide RNA or DNA, respectively. Since all... (Review)
Review
Argonaute (AGO) proteins in all three domains of life form ribonucleoprotein or deoxyribonucleoprotein complexes by loading a guide RNA or DNA, respectively. Since all AGOs retain a PIWI domain that takes an RNase H fold, the ancestor was likely an endoribonuclease (i.e., a slicer). In animals, most miRNA-mediated gene silencing occurs slicer independently. However, the slicer activity of AGO is indispensable in specific events, such as development and differentiation, which are critical for vertebrates and thus cannot be replaced by the slicer-independent regulation. This review highlights the distinctions in catalytic activation mechanisms among slicing-competent AGOs, shedding light on the roles of two metal ions in target recognition and cleavage. The precision of the target specificity by the RNA-induced silencing complexes is reevaluated and redefined. The possible coevolutionary relationship between slicer-independent gene regulation and AGO-binding protein, GW182, is also explored. These discussions reveal that numerous captivating questions remain unanswered regarding the timing and manner in which AGOs employ their slicing activity.
Topics: Animals; Argonaute Proteins; Ribonucleases; RNA, Guide, CRISPR-Cas Systems; RNA, Small Interfering; RNA-Induced Silencing Complex
PubMed: 38029964
DOI: 10.1016/j.jbc.2023.105499 -
Trends in Biochemical Sciences Nov 2022The antiviral defense directed by the RNAi pathway employs distinct specificity and effector mechanisms compared with other immune responses. The specificity of... (Review)
Review
The antiviral defense directed by the RNAi pathway employs distinct specificity and effector mechanisms compared with other immune responses. The specificity of antiviral RNAi is programmed by siRNAs processed from virus-derived double-stranded RNA by Dicer endonuclease. Argonaute-containing RNA-induced silencing complex loaded with the viral siRNAs acts as the effector to mediate specific virus clearance by RNAi. Recent studies have provided evidence for the production and antiviral function of virus-derived siRNAs in both undifferentiated and differentiated mammalian cells infected with a range of RNA viruses when the cognate virus-encoded suppressor of RNAi (VSR) is rendered nonfunctional. In this review, we discuss the function, mechanism, and evolutionary origin of the validated mammalian VSRs and cell culture assays for their identification.
Topics: Animals; Antiviral Agents; Argonaute Proteins; Mammals; RNA Interference; RNA, Double-Stranded; RNA, Small Interfering; RNA, Viral
PubMed: 35618579
DOI: 10.1016/j.tibs.2022.05.001 -
Molecules and Cells Dec 2019PIWI Argonaute proteins and Piwi-interacting RNAs (piRNAs) are expressed in all animal species and play a critical role in cellular defense by inhibiting the activation... (Review)
Review
PIWI Argonaute proteins and Piwi-interacting RNAs (piRNAs) are expressed in all animal species and play a critical role in cellular defense by inhibiting the activation of transposable elements in the germline. Recently, new evidence suggests that PIWI proteins and piRNAs also play important roles in various somatic tissues, including neurons. This review summarizes the neuronal functions of the PIWI-piRNA pathway in multiple animal species, including their involvement in axon regeneration, behavior, memory formation, and transgenerational epigenetic inheritance of adaptive memory. This review also discusses the consequences of dysregulation of neuronal PIWI-piRNA pathways in certain neurological disorders, including neurodevelopmental and neurodegenerative diseases. A full understanding of neuronal PIWI-piRNA pathways will ultimately provide novel insights into small RNA biology and could potentially provide precise targets for therapeutic applications.
Topics: Animals; Argonaute Proteins; Epigenesis, Genetic; Gene Expression Regulation; Humans; Learning; Nerve Regeneration; Nervous System Diseases; Neurons; RNA, Small Interfering
PubMed: 31838836
DOI: 10.14348/molcells.2019.0241