Mechanism of Down-regulation of RNA Polymerase III-transcribed Non-coding RNA Genes in Macrophages by Leishmania

Rana, Tanu; Misra, Smita; Mittal, Mahesh Kumar; Farrow, Anitra L.; Wilson, Keith T.; Linton, MacRae F.; Fazio, Sergio; Willis, Ian M.; Chaudhuri, Gautam

doi:10.1074/jbc.m110.181735

Cited by 23 publications

(16 citation statements)

References 71 publications

(72 reference statements)

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“…It has been shown that infection of macrophages with the parasitic protozoan Leishmania leads to decreased expression of certain Pol III products, including tRNA and 7SL RNA (55,56). Downregulation of 7SL RNA suppresses vesicular trafficking and makes macrophages more susceptible to parasitism.…”

Section: Discussionmentioning

confidence: 99%

Involvement of RNA Polymerase III in Immune Responses

Graczyk

White

Ryan

2015

Molecular and Cellular Biology

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bInflammation in the tumor microenvironment has many tumor-promoting effects. In particular, tumor-associated macrophages (TAMs) produce many cytokines which can support tumor growth by promoting survival of malignant cells, angiogenesis, and metastasis. Enhanced cytokine production by TAMs is tightly coupled with protein synthesis. In turn, translation of proteins depends on tRNAs, short abundant transcripts that are made by RNA polymerase III (Pol III). Here, we connect these facts by showing that stimulation of mouse macrophages with lipopolysaccharides (LPS) from the bacterial cell wall causes transcriptional upregulation of tRNA genes. The transcription factor NF-B is a key transcription factor mediating inflammatory signals, and we report that LPS treatment causes an increased association of the NF-B subunit p65 with tRNA genes. In addition, we show that p65 can directly associate with the Pol III transcription factor TFIIIB and that overexpression of p65 induces Pol IIIdependent transcription. As a consequence of these effects, we show that inhibition of Pol III activity in macrophages restrains cytokine secretion and suppresses phagocytosis, two key functional characteristics of these cells. These findings therefore identify a radical new function for Pol III in the regulation of macrophage function which may be important for the immune responses associated with both normal and malignant cells.

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Section: Discussionmentioning

confidence: 99%

Involvement of RNA Polymerase III in Immune Responses

Graczyk

White

Ryan

2015

Molecular and Cellular Biology

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“…Virulent Leishmania infection of macrophages results in the degradation of the TFIIIC110 subunit through thrombin receptor-mediated activation of the protease μ-calpain. This leads to a decrease in functional TFIIIC and the loss of pol III transcription of genes containing tRNA-type promoters [89]. …”

Section: Targets For Regulation Of Pol III Transcriptionmentioning

confidence: 99%

Regulation of pol III transcription by nutrient and stress signaling pathways

Moir

Willis

2013

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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126

125

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Transcription by RNA polymerase III (pol III) is responsible for ~15% of total cellular transcription through the generation of small structured RNAs such as tRNA and 5S RNA. The coordinate synthesis of these molecules with ribosomal protein mRNAs and rRNA couples the production of ribosomes and their tRNA substrates and balances protein synthetic capacity with the growth requirements of the cell. Ribosome biogenesis in general and pol III transcription in particular is known to be regulated by nutrient availability, cell stress and cell cycle stage and is perturbed in pathological states. High throughput proteomic studies have catalogued modifications to pol III subunits, assembly, initiation and accessory factors but most of these modifications have yet to be linked to functional consequences. Here we review our current understanding of the major points of regulation in the pol III transcription apparatus, the targets of regulation and the signaling pathways known to regulate their function.

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“…Similar to other eukaryotes, transcription initiation by RNA polymerase I and III occurs at defined core promoters in trypanosomatids [11], [12], [13]. Canonical signals for RNA polymerase II recruitment have been characterized for the promoters of spliced leader, (SL) genes [14], [15], but not for the transcription of genes contained within the directional gene clusters (DGCs).…”

Section: Introductionmentioning

confidence: 99%

Genomic Analysis of Sequence-Dependent DNA Curvature in Leishmania

Smircich

Forteza²,

El-Sayed

et al. 2013

PLoS ONE

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Leishmania major is a flagellated protozoan parasite of medical importance. Like other members of the Trypanosomatidae family, it possesses unique mechanisms of gene expression such as constitutive polycistronic transcription of directional gene clusters, gene amplification, mRNA trans-splicing, and extensive editing of mitochondrial transcripts. The molecular signals underlying most of these processes remain under investigation. In order to investigate the role of DNA secondary structure signals in gene expression, we carried out a genome-wide in silico analysis of the intrinsic DNA curvature. The L. major genome revealed a lower frequency of high intrinsic curvature regions as well as inter- and intra- chromosomal distribution heterogeneity, when compared to prokaryotic and eukaryotic organisms. Using a novel method aimed at detecting region-integrated intrinsic curvature (RIIC), high DNA curvature was found to be associated with regions implicated in transcription initiation. Those include divergent strand-switch regions between directional gene clusters and regions linked to markers of active transcription initiation such as acetylated H3 histone, TRF4 and SNAP50. These findings suggest a role for DNA curvature in transcription initiation in Leishmania supporting the relevance of DNA secondary structures signals.

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Mechanism of Down-regulation of RNA Polymerase III-transcribed Non-coding RNA Genes in Macrophages by Leishmania

Cited by 23 publications

References 71 publications

Involvement of RNA Polymerase III in Immune Responses

Involvement of RNA Polymerase III in Immune Responses

Regulation of pol III transcription by nutrient and stress signaling pathways

Genomic Analysis of Sequence-Dependent DNA Curvature in Leishmania

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