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Bioconjugate Chemistry Jan 2021Since its conception, the ribonuclease S complex (RNase S) has led to historic discoveries in protein chemistry, enzymology, and related fields. Derived by the...
Since its conception, the ribonuclease S complex (RNase S) has led to historic discoveries in protein chemistry, enzymology, and related fields. Derived by the proteolytic cleavage of a single peptide bond in bovine pancreatic ribonuclease (RNase A), RNase S serves as a convenient and reliable model system for incorporating unlimited functionality into an enzyme. Applications of the RNase S system in biomedicine and biotechnology have, however, been hindered by two shortcomings: (1) the bovine-derived enzyme could elicit an immune response in humans, and (2) the complex is susceptible to dissociation. Here, we have addressed both limitations in the first semisynthesis of an RNase S conjugate derived from human pancreatic ribonuclease and stabilized by a covalent interfragment cross-link. We anticipate that this strategy will enable unprecedented applications of the "RNase-S" system.
Topics: Amino Acid Sequence; Electrophoresis, Polyacrylamide Gel; Humans; Ribonuclease, Pancreatic; Ribonucleases; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
PubMed: 33296182
DOI: 10.1021/acs.bioconjchem.0c00557 -
Critical Reviews in Biochemistry and... Jun 2022Pancreatic-type ribonucleases (ptRNases) are a large family of vertebrate-specific secretory endoribonucleases. These enzymes catalyze the degradation of many RNA... (Review)
Review
Pancreatic-type ribonucleases (ptRNases) are a large family of vertebrate-specific secretory endoribonucleases. These enzymes catalyze the degradation of many RNA substrates and thereby mediate a variety of biological functions. Though the homology of ptRNases has informed biochemical characterization and evolutionary analyses, the understanding of their biological roles is incomplete. Here, we review the functions of two ptRNases: RNase 1 and angiogenin. RNase 1, which is an abundant ptRNase with high catalytic activity, has newly discovered roles in inflammation and blood coagulation. Angiogenin, which promotes neovascularization, is now known to play roles in the progression of cancer and amyotrophic lateral sclerosis, as well as in the cellular stress response. Ongoing work is illuminating the biology of these and other ptRNases.
Topics: Endoribonucleases; RNA; Ribonuclease, Pancreatic; Ribonucleases
PubMed: 34886717
DOI: 10.1080/10409238.2021.2004577 -
FEMS Microbiology Reviews Sep 2023Bacteria adjust gene expression at the post-transcriptional level through an intricate network of small regulatory RNAs and RNA-binding proteins, including ribonucleases... (Review)
Review
Bacteria adjust gene expression at the post-transcriptional level through an intricate network of small regulatory RNAs and RNA-binding proteins, including ribonucleases (RNases). RNases play an essential role in RNA metabolism, regulating RNA stability, decay, and activation. These enzymes exhibit species-specific effects on gene expression, bacterial physiology, and different strategies of target recognition. Recent advances in high-throughput RNA sequencing (RNA-seq) approaches have provided a better understanding of the roles and modes of action of bacterial RNases. Global studies aiming to identify direct targets of RNases have highlighted the diversity of RNase activity and RNA-based mechanisms of gene expression regulation. Here, we review recent RNA-seq approaches used to study bacterial RNases, with a focus on the methods for identifying direct RNase targets.
Topics: Ribonucleases; RNA-Seq; Endoribonucleases; Bacteria; RNA
PubMed: 37656885
DOI: 10.1093/femsre/fuad049 -
American Journal of Physiology. Renal... May 2021Antimicrobial peptides are essential host defense mechanisms that prevent urinary tract infections. Recent studies have demonstrated that peptides in the ribonuclease A...
Antimicrobial peptides are essential host defense mechanisms that prevent urinary tract infections. Recent studies have demonstrated that peptides in the ribonuclease A superfamily have antimicrobial activity against uropathogens and protect the urinary tract from uropathogenic (UPEC). Little is known about the antibacterial function or expression of ribonuclease 4 (RNase 4) in the human urinary tract. Here, we show that full-length recombinant RNase 4 peptide and synthetic amino-terminal RNase 4 peptide fragment have antibacterial activity against UPEC and multidrug-resistant (MDR)-UPEC. transcript expression was detected in human kidney and bladder tissue using quantitative real-time PCR. Immunostaining or in situ hybridization localized RNase 4 expression to proximal tubules, principal and intercalated cells in the kidney's collecting duct, and the bladder urothelium. Urinary RNase 4 concentrations were quantified in healthy controls and females with a history of urinary tract infection. Compared with controls, urinary RNase 4 concentrations were significantly lower in females with a history of urinary tract infection. When RNase 4 was neutralized in human urine or silenced in vitro using siRNA, urinary UPEC replication or attachment to and invasion of urothelial and kidney medullary cells increased. These data show that RNase 4 has antibacterial activity against UPEC, is expressed in the human urinary tract, and can contribute to host defense against urinary tract infections. Ribonuclease 4 (RNase 4) is a newly identified host defense peptide in the human kidney and bladder. RNase 4 kills uropathogenic (UPEC) and multidrug-resistant UPEC. RNase 4 prevents invasive UPEC infection and suppressed RNase 4 expression may be a risk factor for more severe or recurrent urinary tract infection.
Topics: Adolescent; Antimicrobial Cationic Peptides; Child; Endothelial Cells; Female; Gene Expression Regulation, Enzymologic; Gene Silencing; History, Ancient; History, Medieval; Humans; Kidney; Real-Time Polymerase Chain Reaction; Ribonucleases; Urinary Bladder; Uropathogenic Escherichia coli; Urothelium
PubMed: 33818125
DOI: 10.1152/ajprenal.00592.2020 -
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 -
Protein Science : a Publication of the... Apr 2020PhoH2 proteins are found in a very diverse range of microorganisms that span bacteria and archaea. These proteins are composed of two domains: an N-terminal PIN-domain... (Review)
Review
PhoH2 proteins are found in a very diverse range of microorganisms that span bacteria and archaea. These proteins are composed of two domains: an N-terminal PIN-domain fused with a C-terminal PhoH domain. Collectively this fusion functions as an RNA helicase and ribonuclease. In other genomic contexts, PINdomains and PhoHdomains are separate but adjacent suggesting association to achieve similar function. Exclusively among the mycobacteria, PhoH2 proteins are encoded in the genome with an upstream gene, phoAT, which is thought to play the role of an antitoxin (in place of the traditional VapB antitoxin that lies upstream of the 47 other PINdomains in the mycobacterial genome). This review examines PhoH2 proteins as a whole and describes the bioinformatics, biochemical, structural, and biological properties of the two domains that make up PhoH2: PIN and PhoH. We review the transcriptional regulators of phoH2 from two mycobacterial species and speculate on the function of PhoH2 proteins in the context of a Type II toxin-antitoxin system which are thought to play a role in the stress response in bacteria.
Topics: Bacterial Proteins; RNA Helicases; Ribonucleases
PubMed: 31886915
DOI: 10.1002/pro.3814 -
BioMed Research International 2014Sialic acid-binding lectin (SBL), isolated from oocytes of Rana catesbeiana, is leczyme and has both lectin and ribonuclease (RNase) activities. A remarkable antitumor... (Review)
Review
Sialic acid-binding lectin (SBL), isolated from oocytes of Rana catesbeiana, is leczyme and has both lectin and ribonuclease (RNase) activities. A remarkable antitumor effect of SBL has also been reported. SBL agglutinates various kinds of tumor cells but not normal cells. SBL agglutination activity is not affected by mono- or oligosaccharides. However, SBL-induced agglutination and antitumor effects are inhibited by sialomucin but not asialomucin. In addition, SBL has very little effect on sialidase-treated cells. SBL causes cancer-selective induction of apoptosis by multiple signaling pathways, which target RNA. Synergistic antitumor effects with other molecules, such as tumor necrosis factor-related apoptosis ligand (TRAIL) and interferon- γ (IFN-γ), have been reported. Thus, SBL may be a novel candidate molecule for anticancer drug development. Sialoglycoconjugates on the tumor cell surface may be associated with lectin activity and antitumor effects of SBL. We review the properties of SBL, particularly its lectin, RNase, and antitumor activities, and comprehensively examine the potential application of SBL for clinical purposes.
Topics: Amino Acid Sequence; Amphibian Proteins; Animals; Antineoplastic Agents; Cell Membrane; Drug Screening Assays, Antitumor; Lectins; Molecular Sequence Data; Neoplasms; Rana catesbeiana; Ribonucleases
PubMed: 24864241
DOI: 10.1155/2014/421415 -
ACS Chemical Biology Oct 2023Ribonucleases (RNases) cleave and process RNAs, thereby regulating the biogenesis, metabolism, and degradation of coding and noncoding RNAs. Thus, small molecules... (Review)
Review
Ribonucleases (RNases) cleave and process RNAs, thereby regulating the biogenesis, metabolism, and degradation of coding and noncoding RNAs. Thus, small molecules targeting RNases have the potential to perturb RNA biology, and RNases have been studied as therapeutic targets of antibiotics, antivirals, and agents for autoimmune diseases and cancers. Additionally, the recent advances in chemically induced proximity approaches have led to the discovery of bifunctional molecules that target RNases to achieve RNA degradation or inhibit RNA processing. Here, we summarize the efforts that have been made to discover small-molecule inhibitors and activators targeting bacterial, viral, and human RNases. We also highlight the emerging examples of RNase-targeting bifunctional molecules and discuss the trends in developing such molecules for both biological and therapeutic applications.
Topics: Humans; Ribonucleases; Endoribonucleases; RNA; Ribonuclease, Pancreatic; Neoplasms
PubMed: 37382390
DOI: 10.1021/acschembio.3c00191 -
Biomedical Journal 2014Zucchini (Zuc), a member of the phospholipase D (PLD) superfamily, is essential for the primary PIWI-interacting RNA (piRNA) biogenesis and the suppression of transposon... (Review)
Review
Zucchini (Zuc), a member of the phospholipase D (PLD) superfamily, is essential for the primary PIWI-interacting RNA (piRNA) biogenesis and the suppression of transposon expression, which are crucial for the genome integrity of germline cells. However, it has been ambiguous whether Zuc acts as a phosphodiesterase to produce phosphatidic acid (PA), the lipid signaling molecule, or as a nuclease. The recent three papers describing the crystal structures and functional analyses of fly and mouse Zuc proteins have elucidated that Zuc is a PLD family single-strand ribonuclease, not a phosphodiesterase, and functions in the maturation of primary piRNAs. This review will discuss in detail how the crystal structures clearly predict the function of Zuc, which is subsequently demonstrated by biochemical analysis to conclude the previous controversial discussion on the real function of Zuc.
Topics: Animals; Crystallography, X-Ray; Drosophila Proteins; Drosophila melanogaster; Endoribonucleases; Humans; Phosphoric Diester Hydrolases; Ribonucleases
PubMed: 25179713
DOI: 10.4103/2319-4170.132909 -
International Journal of Molecular... Mar 2016The Ribonuclease A Superfamily is composed of a group of structurally similar peptides that are secreted by immune cells and epithelial tissues. Several members of the... (Review)
Review
The Ribonuclease A Superfamily is composed of a group of structurally similar peptides that are secreted by immune cells and epithelial tissues. Several members of the Ribonuclease A Superfamily demonstrate antimicrobial activity, and it has been suggested that some of these ribonucleases play an essential role in host defense. Ribonuclease 7 (RNase 7) is an epithelial-derived secreted peptide with potent broad-spectrum antimicrobial activity. This review summarizes the published literature on RNase 7's antimicrobial properties, structure, regulation, and contributions to host defense. In doing so, we conclude by highlighting key knowledge gaps that must be investigated to completely understand the potential of developing RNase 7 as a novel therapeutic for human infectious diseases.
Topics: Animals; Humans; Immunity, Innate; Ribonucleases
PubMed: 27011175
DOI: 10.3390/ijms17030423