Ribonucleases as Drug Targets

Canestrari, Emanuele; Paroo, Zain

doi:10.1016/j.tips.2018.07.005

Cited by 15 publications

(11 citation statements)

References 88 publications

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“…The post-transcriptional regulation of mRNA stability is an important checkpoint for gene expression, and ribonucleases play a central role in this process. Consequently, abnormalities in ribonucleases have been associated with multiple disease [12,27,28]. Indeed, we previously demonstrated that ZFP36L1, an RNAbinding protein that binds to AU-rich elements (AREs) in the 3'-UTRs of its target mRNAs, regulates OA pathogenesis by modulating the mRNA decay of HSP70 family members [29].…”

Section: Discussionmentioning

confidence: 99%

Up-regulated Endonuclease Regnase-1 Suppresses Osteoarthritis by Forming Negative Feedback Loop of Catabolic Signaling in Chondrocytes

Yang

Chun

2020

Preprint

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Background: Ribonucleases (RNases) play central roles in the post-transcriptional regulation of mRNA stability. Our preliminary results revealed that the endonuclease Regnase-1 is specifically up-regulated in osteoarthritic chondrocytes. We herein explored the possible functions and regulatory mechanisms of Regnase-1 in a mouse model of osteoarthritis (OA).Methods: The expression and target genes of Regnase-1 were identified by microarray analysis in primary-culture mouse articular chondrocytes. Experimental OA in mice was induced by destabilization of the medial meniscus (DMM). The function of Regnase-1 in DMM-induced post-traumatic OA mice was examined by adenovirus-mediated overexpression or knockdown in knee joint tissues, and also by using Regnase-1 heterozygous knockout mice (Zc3h12a+/-). Results: Among the RNases, Regnase-1 was exclusively up-regulated in chondrocytes stimulated with OA-associated catabolic factors. Adenovirus-mediated overexpression or knockdown of Regnase-1 alone in joint tissues did not cause OA-like changes. However, overexpression of Regnase-1 in joint tissues significantly ameliorated DMM-induced post-traumatic OA cartilage destruction, whereas knockdown or genetic ablation of Regnase-1 exacerbated DMM-induced cartilage destruction. Mechanistic studies showed that Regnase-1 appears to suppress cartilage destruction by modulating the expression of matrix-degrading enzymes in chondrocytes. Conclusion: Our results collectively suggest that up-regulated Regnase-1 in OA chondrocytes may function as a chondro-protective effector molecule during OA pathogenesis by forming negative feedback loop of catabolic signaling such as expression of matrix-degrading enzymes in OA chondrocytes.

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Section: Discussionmentioning

confidence: 99%

Up-regulated Endonuclease Regnase-1 Suppresses Osteoarthritis by Forming Negative Feedback Loop of Catabolic Signaling in Chondrocytes

Yang

Chun

2020

Preprint

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“…However, as a control, RNase A cleaved ssRNAs mainly produce pyrimidineterminated nucleotide fragments, which cannot match the second binding pocket of TLR8. This study provides an interesting peek into the role of RNase T2 in resisting bacterial infections via its immunomodulatory functions ( Figure 2) (3,24). Similarly, RNase T2 secreted by eggs of Schistosoma mansoni, i.e., omega-1, can promote the polarization of CD4 + T cells to Th2 through dendritic cells (DCs) (56,57).…”

Section: Rnase T2 In Inflammationmentioning

confidence: 91%

“…However, as a control, RNase A cleaved ssRNAs mainly produce pyrimidine-terminated nucleotide fragments, which cannot match the second binding pocket of TLR8. This study provides an interesting peek into the role of RNase T2 in resisting bacterial infections via its immunomodulatory functions ( Figure 2 ) ( 3 , 24 ).…”

Section: Rnase T2 In Inflammationmentioning

confidence: 99%

“…For instance, RNase T2 acts as a tumor suppressor in a variety of cancers, such as colorectal cancer, ovarian tumors, melanoma, and non-Hodgkin's B-cell lymphoma and acute lymphoblastic leukemia (20)(21)(22)(23). Hence, the RNase T2 family is receiving an increasing amount of attention due to its key roles in inflammation and cancer (3,(24)(25)(26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

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RNase T2 in Inflammation and Cancer: Immunological and Biological Views

Zhao

et al. 2020

Front. Immunol.

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The RNase T2 family consists of evolutionarily conserved endonucleases that express in many different species, including animals, plants, protozoans, bacteria, and viruses. The main biological roles of these ribonucleases are cleaving or degrading RNA substrates. They preferentially cleave single-stranded RNA molecules between purine and uridine residues to generate two nucleotide fragments with 2'3'-cyclic phosphate adenosine/guanosine terminus and uridine residue, respectively. Accumulating studies have revealed that RNase T2 is critical for the pathophysiology of inflammation and cancer. In this review, we introduce the distribution, structure, and functions of RNase T2, its differential roles in inflammation and cancer, and the perspective for its research and related applications in medicine.

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“…One mechanism for achieving this is regulation of gene expression through the differential processing and/or turnover of RNAs by ribonucleases (RNases) 1 . The importance of RNases in these processes is underlined by the roles that they play in pathogenic bacterial virulence 2 and, as a consequence, RNases are emerging as attractive antibacterial drug targets 2–4 . For example, the endoribonuclease RNase E is essential for cell viability in Escherichia coli 5–7 where roles in mRNA decay and the maturation of tRNA and rRNA have been well documented [reviewed in 1 and 8 ].…”

Section: Introductionmentioning

confidence: 99%

A structural and biochemical comparison of Ribonuclease E homologues from pathogenic bacteria highlights species-specific properties

Mardle

Shakespeare

Butt

et al. 2019

Sci Rep

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Regulation of gene expression through processing and turnover of RNA is a key mechanism that allows bacteria to rapidly adapt to changing environmental conditions. Consequently, RNA degrading enzymes (ribonucleases; RNases) such as the endoribonuclease RNase E, frequently play critical roles in pathogenic bacterial virulence and are potential antibacterial targets. RNase E consists of a highly conserved catalytic domain and a variable non-catalytic domain that functions as the structural scaffold for the multienzyme degradosome complex. Despite conservation of the catalytic domain, a recent study identified differences in the response of RNase E homologues from different species to the same inhibitory compound(s). While RNase E from Escherichia coli has been well-characterised, far less is known about RNase E homologues from other bacterial species. In this study, we structurally and biochemically characterise the RNase E catalytic domains from four pathogenic bacteria: Yersinia pestis , Francisella tularensis , Burkholderia pseudomallei and Acinetobacter baumannii , with a view to exploiting RNase E as an antibacterial target. Bioinformatics, small-angle x-ray scattering and biochemical RNA cleavage assays reveal globally similar structural and catalytic properties. Surprisingly, subtle species-specific differences in both structure and substrate specificity were also identified that may be important for the development of effective antibacterial drugs targeting RNase E.

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Ribonucleases as Drug Targets

Cited by 15 publications

References 88 publications

Up-regulated Endonuclease Regnase-1 Suppresses Osteoarthritis by Forming Negative Feedback Loop of Catabolic Signaling in Chondrocytes

Up-regulated Endonuclease Regnase-1 Suppresses Osteoarthritis by Forming Negative Feedback Loop of Catabolic Signaling in Chondrocytes

RNase T2 in Inflammation and Cancer: Immunological and Biological Views

A structural and biochemical comparison of Ribonuclease E homologues from pathogenic bacteria highlights species-specific properties

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