A KLF4-miRNA-206 Autoregulatory Feedback Loop Can Promote or Inhibit Protein Translation Depending upon Cell Context

Ribosome-inactivating proteins (RIPs) are a class of cytotoxic enzymes that can inhibit protein translation by depurinating rRNA. Most plant RIPs are synthesized with a leader sequence that sequesters the proteins to a cell compartment away from the host ribosomes. However, several rice RIPs lack these signal peptides suggesting they reside in the cytosol in close proximity to the plant ribosomes. This paper aims to elucidate the physiological function of two nucleocytoplasmic RIPs from rice, in particular, the type 1 RIP referred to as OsRIP1 and a presumed type 3 RIP called nuRIP. Transgenic rice lines overexpressing these RIPs were constructed and studied for developmental effects resulting from this overexpression under greenhouse conditions. In addition, the performance of transgenic seedlings in response to drought, salt, abscisic acid and methyl jasmonate treatment was investigated. Results suggest that both RIPs can affect methyl jasmonate mediated stress responses.

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Small RNAs derived from the 5′ end of tRNA can inhibit protein translation in human cells

RNA Biology ◽

10.4161/rna.24285 ◽

2013 ◽

Vol 10 (4) ◽

pp. 553-563 ◽

Cited By ~ 169

Author(s):

Andrew Sobala ◽

Gyorgy Hutvagner

Keyword(s):

Small Rnas ◽

Protein Translation ◽

Human Cells ◽

Inhibit Protein Translation

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XIAP Interaction with E2F1 and Sp1 via its BIR2 and BIR3 domains specific activated MMP2 to promote bladder cancer invasion

Oncogenesis ◽

10.1038/s41389-019-0181-8 ◽

2019 ◽

Vol 8 (12) ◽

Cited By ~ 4

Author(s):

Jiheng Xu ◽

Xiaohui Hua ◽

Rui Yang ◽

Honglei Jin ◽

Jingxia Li ◽

...

Keyword(s):

Bladder Cancer ◽

Cell Invasion ◽

Feedback Loop ◽

Ectopic Expression ◽

Direct Interaction ◽

Protein Translation ◽

Negative Regulator ◽

Cancer Cell Invasion ◽

Design Synthesis ◽

First Time

AbstractXIAP has generally been thought to function in bladder cancer. However, the potential function of structure-based function of XIAP in human BC invasion has not been well explored before. We show here that ectopic expression of the BIR domains of XIAP specifically resulted in MMP2 activation and cell invasion in XIAP-deleted BC cells, while Src was further defined as an XIAP downstream negative regulator for MMP2 activation and BC cell invasion. The inhibition of Src expression by the BIR domains was caused by attenuation of Src protein translation upon miR-203 upregulation; which was resulted from direct interaction of BIR2 and BIR3 with E2F1 and Sp1, respectively. The interaction of BIR2/BIR3 with E2F1/Sp1 unexpectedly occurred, which could be blocked by serum-induced XIAP translocation. Taken together, our studies, for the first time revealed that: (1) BIR2 and BIR3 domains of XIAP play their role in cancer cell invasion without affecting cell migration by specific activation of MMP2 in human BC cells; (2) by BIR2 interacting with E2F1 and BIR3 interacting with Sp1, XIAP initiates E2F1/Sp1 positive feedback loop-dependent transcription of miR-203, which in turn inhibits Src protein translation, further leading to MMP2-cleaved activation; (3) XIAP interaction with E2F1 and Sp1 is observed in the nucleus. Our findings provide novel insights into understanding the specific function of BIR2 and BIR3 of XIAP in BC invasion, which will be highly significant for the design/synthesis of new BIR2/BIR3-based compounds for invasive BC treatment.

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Transcriptome-based design of antisense inhibitors potentiates carbapenem efficacy in CREEscherichia coli

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1922187117 ◽

2020 ◽

Vol 117 (48) ◽

pp. 30699-30709

Author(s):

Thomas R. Aunins ◽

Keesha E. Erickson ◽

Anushree Chatterjee

Keyword(s):

Gene Expression ◽

Protein Translation ◽

Resistance Mechanisms ◽

Transcriptomic Analysis ◽

Gene Expression Response ◽

Antibiotic Development ◽

Resistance Factors ◽

Inhibit Protein Translation ◽

Significant Expression ◽

Expression Response

In recent years, the prevalence of carbapenem-resistantEnterobacteriaceae(CRE) has risen substantially, and the study of CRE resistance mechanisms has become increasingly important for antibiotic development. Although much research has focused on genomic resistance factors, relatively few studies have examined CRE pathogens through changes in gene expression. In this study, we examined the gene expression profile of a CREEscherichia coliclinical isolate that is sensitive to meropenem but resistant to ertapenem to explore transcriptomic contributions to resistance and to identify gene knockdown targets for carbapenem potentiation. We sequenced total and short RNA to analyze the gene expression response to ertapenem or meropenem treatment and found significant expression changes in genes related to motility, maltodextrin metabolism, the formate hydrogenlyase complex, and the general stress response. To validate these findings, we used our laboratory’s Facile Accelerated Specific Therapeutic (FAST) platform to create antisense peptide nucleic acids (PNAs), gene-specific molecules designed to inhibit protein translation. PNAs were designed to inhibit the pathways identified in our transcriptomic analysis, and each PNA was then tested in combination with each carbapenem to assess its effect on the antibiotics’ minimum inhibitory concentrations. We observed significant PNA–antibiotic interaction with five different PNAs across six combinations. Inhibition of the geneshycA,dsrB, andbolApotentiated carbapenem efficacy in CREE. coli, whereas inhibition of the genesflhCandygaCconferred added resistance. Our results identify resistance factors and demonstrate that transcriptomic analysis is a potent tool for designing antibiotic PNA.

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A highly conserved G-rich consensus sequence in hepatitis C virus core gene represents a new anti–hepatitis C target

Science Advances ◽

10.1126/sciadv.1501535 ◽

2016 ◽

Vol 2 (4) ◽

pp. e1501535 ◽

Cited By ~ 49

Author(s):

Shao-Ru Wang ◽

Yuan-Qin Min ◽

Jia-Qi Wang ◽

Chao-Xing Liu ◽

Bo-Shi Fu ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Consensus Sequence ◽

Protein Translation ◽

Core Gene ◽

Consensus Sequences ◽

Virus Core ◽

New Strategy ◽

Inhibit Protein Translation

G-quadruplex (G4) is one of the most important secondary structures in nucleic acids. Until recently, G4 RNAs have not been reported in any ribovirus, such as the hepatitis C virus. Our bioinformatics analysis reveals highly conserved guanine-rich consensus sequences within the core gene of hepatitis C despite the high genetic variability of this ribovirus; we further show using various methods that such consensus sequences can fold into unimolecular G4 RNA structures, both in vitro and under physiological conditions. Furthermore, we provide direct evidences that small molecules specifically targeting G4 can stabilize this structure to reduce RNA replication and inhibit protein translation of intracellular hepatitis C. Ultimately, the stabilization of G4 RNA in the genome of hepatitis C represents a promising new strategy for anti–hepatitis C drug development.

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Cryo-EM structure of the Plasmodium falciparum 80S ribosome bound to the anti-protozoan drug emetine

eLife ◽

10.7554/elife.03080 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 161

Author(s):

Wilson Wong ◽

Xiao-chen Bai ◽

Alan Brown ◽

Israel S Fernandez ◽

Eric Hanssen ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Protein Translation ◽

Small Subunit ◽

80S Ribosome ◽

Human Malaria Parasite ◽

Parasite Plasmodium ◽

Parasite Plasmodium Falciparum ◽

Inhibit Protein Translation ◽

Trna Translocation ◽

Approved Drugs

Malaria inflicts an enormous burden on global human health. The emergence of parasite resistance to front-line drugs has prompted a renewed focus on the repositioning of clinically approved drugs as potential anti-malarial therapies. Antibiotics that inhibit protein translation are promising candidates for repositioning. We have solved the cryo-EM structure of the cytoplasmic ribosome from the human malaria parasite, Plasmodium falciparum, in complex with emetine at 3.2 Å resolution. Emetine is an anti-protozoan drug used in the treatment of ameobiasis that also displays potent anti-malarial activity. Emetine interacts with the E-site of the ribosomal small subunit and shares a similar binding site with the antibiotic pactamycin, thereby delivering its therapeutic effect by blocking mRNA/tRNA translocation. As the first cryo-EM structure that visualizes an antibiotic bound to any ribosome at atomic resolution, this establishes cryo-EM as a powerful tool for screening and guiding the design of drugs that target parasite translation machinery.

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Structure and Activity of a Cytosolic Ribosome-Inactivating Protein from Rice

Toxins ◽

10.3390/toxins11060325 ◽

2019 ◽

Vol 11 (6) ◽

pp. 325 ◽

Cited By ~ 1

Author(s):

Jeroen De Zaeytijd ◽

Pierre Rougé ◽

Guy Smagghe ◽

Els J.M. Van Damme

Keyword(s):

Physiological Role ◽

Protein Translation ◽

Suspension Cells ◽

Ribosome Inactivating Proteins ◽

Inhibit Protein Translation ◽

Plant Ribosomes ◽

First Time

Ribosome-inactivating proteins (RIPs) are cytotoxic enzymes that inhibit protein translation by depurinating ribosomal RNA. Although most plant RIPs are synthesized with leader sequences that sequester them away from the host ribosomes, several RIPs from cereals lack these signal peptides and therefore probably reside in the cytosol near the plant ribosomes. More than 30 RIP genes have been identified in the rice (Oryza sativa spp. japonica) genome, many of them lacking a signal peptide. This paper focuses on a presumed cytosolic type-1 RIP from rice, referred to as OsRIP1. Using 3D modeling it is shown that OsRIP1 structurally resembles other cereal RIPs and has an active site that meets the requirements for activity. Furthermore, localization studies indicate that OsRIP1-eGFP fusion proteins reside in the nucleocytoplasmic space when expressed in epidermal cells of Nicotiana benthamiana or Arabidopsis thaliana suspension cells. Finally, OsRIP1 was recombinantly produced in Escherichia coli and was demonstrated to possess catalytic activity. Interestingly, this recombinant RIP inactivates wheat ribosomes far less efficiently than rabbit ribosomes in an in vitro system. These findings raise some interesting questions concerning the mode of action and physiological role of OsRIP1. This is the first time a RIP from rice is investigated at protein level and is shown to possess biological activity.

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Cytochrome P450 1B1 mRNA untranslated regions interact to inhibit protein translation

Molecular Carcinogenesis ◽

10.1002/mc.20589 ◽

2009 ◽

Vol 49 (2) ◽

pp. 190-199 ◽

Cited By ~ 13

Author(s):

Andrea H. Devlin ◽

Paul Thompson ◽

Tracy Robson ◽

Stephanie R. McKeown

Keyword(s):

Cytochrome P450 ◽

Protein Translation ◽

Untranslated Regions ◽

Cytochrome P450 1B1 ◽

Inhibit Protein Translation

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hnRNPs and ELAVL1 cooperate with uORFs to inhibit protein translation

Nucleic Acids Research ◽

10.1093/nar/gkw991 ◽

2016 ◽

pp. gkw991 ◽

Cited By ~ 3

Author(s):

Jiewen Zhang ◽

Lijuan Kong ◽

Sichao Guo ◽

Mengmeng Bu ◽

Qian Guo ◽

...

Keyword(s):

Protein Translation ◽

Inhibit Protein Translation

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Novel players fine-tune plant trade-offs

Essays in Biochemistry ◽

10.1042/bse0580083 ◽

2015 ◽

Vol 58 ◽

pp. 83-100 ◽

Cited By ~ 25

Author(s):

Selena Gimenez-Ibanez ◽

Marta Boter ◽

Roberto Solano

Keyword(s):

Ubiquitin Ligase ◽

Feedback Loop ◽

Molecular Level ◽

26S Proteasome ◽

Signalling Molecules ◽

Transcriptional Reprogramming ◽

Trade Offs ◽

Jaz Proteins ◽

Regulatory Feedback Loop ◽

Fine Tune

Jasmonates (JAs) are essential signalling molecules that co-ordinate the plant response to biotic and abiotic challenges, as well as co-ordinating several developmental processes. Huge progress has been made over the last decade in understanding the components and mechanisms that govern JA perception and signalling. The bioactive form of the hormone, (+)-7-iso-jasmonyl-l-isoleucine (JA-Ile), is perceived by the COI1–JAZ co-receptor complex. JASMONATE ZIM DOMAIN (JAZ) proteins also act as direct repressors of transcriptional activators such as MYC2. In the emerging picture of JA-Ile perception and signalling, COI1 operates as an E3 ubiquitin ligase that upon binding of JA-Ile targets JAZ repressors for degradation by the 26S proteasome, thereby derepressing transcription factors such as MYC2, which in turn activate JA-Ile-dependent transcriptional reprogramming. It is noteworthy that MYCs and different spliced variants of the JAZ proteins are involved in a negative regulatory feedback loop, which suggests a model that rapidly turns the transcriptional JA-Ile responses on and off and thereby avoids a detrimental overactivation of the pathway. This chapter highlights the most recent advances in our understanding of JA-Ile signalling, focusing on the latest repertoire of new targets of JAZ proteins to control different sets of JA-Ile-mediated responses, novel mechanisms of negative regulation of JA-Ile signalling, and hormonal cross-talk at the molecular level that ultimately determines plant adaptability and survival.

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