Overproduction of non‐translatable mRNA silences. The transcription of <i>Ty1</i> retrotransposons in <i>S. cerevisiae</i> via functional inactivation of the nuclear cap‐binding complex and subsequent hyperstimulation of the TORC1 pathway

Wu, Xiaofeng; Jiang, Yi

doi:10.1002/yea.1591

Cited by 6 publications

(9 citation statements)

References 82 publications

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“…These transcripts are subsequently degraded through a process called non-sense mediated decay [57]. How increased abundance of truncated transcripts influence cellular response is not exactly clear, however in one such study in an unrelated system, it was shown that non-sense mediated decay cramps the nuclear cap binding protein (NCBP) in an inactive form thereby influencing the cytosolic export of newly formed transcripts [58]. It will be interesting to see whether similar mechanisms are operational in higher eukaryotes as well.…”

Section: Discussionmentioning

confidence: 99%

Alternate splicing of transcripts shape macrophage response to Mycobacterium tuberculosis infection

2017

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Transcriptional reprogramming of macrophages upon Mycobacterium tuberculosis (Mtb) infection is widely studied; however, the significance of alternate splicing (AS) in shaping cellular responses to mycobacterial infections is not yet appreciated. Alternate splicing can influence transcript stability or structure, function and localization of corresponding proteins thereby altering protein stoichiometry and physiological consequences. Using comprehensive analysis of a time-series RNA-seq data obtained from human macrophages infected with virulent or avirulent strains of Mtb, we show extensive remodeling of alternate splicing in macrophage transcriptome. The global nature of this regulation was evident since genes belonging to functional classes like trafficking, immune response, autophagy, redox and metabolism showed marked departure in the pattern of splicing in the infected macrophages. The systemic perturbation of splicing machinery in the infected macrophages was apparent as genes involved at different stages of spliceosome assembly were also regulated at the splicing level. Curiously there was a considerable increase in the expression of truncated/non-translatable variants of several genes, specifically upon virulent infections. Increased expression of truncated transcripts correlated with a decline in the corresponding protein levels. We verified the physiological relevance for one such candidate gene RAB8B; whose truncated variant gets enriched in H37Rv infected cells. Upon tweaking relative abundance of longer or shorter variants of RAB8B transcripts by specialized transduction, mycobacterial targeting to lysosomes could be promoted or blocked respectively, which also resulted in corresponding changes in the bacterial survival. Our results show RAB8B recruitment to the mycobacterial phagosomes is required for phagosome maturation. Thus the abundance of truncated RAB8B variant helps virulent Mtb survival by limiting the RAB8B levels in the cells, a mechanism which we subsequently verified in human primary macrophages. Taken together we demonstrate alternate splicing as a new locus of intervention by Mtb and provide attractive alternative to exploit for novel drug targets against Mtb.

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Section: Discussionmentioning

confidence: 99%

Alternate splicing of transcripts shape macrophage response to Mycobacterium tuberculosis infection

2017

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“…Earlier, we had shown that reporter gene expression driven by the BARE LTR is dependent on the presence of TATA2 and not TATA1 [19,31], strongly suggesting that all translated BARE proteins are derived from TATA2. Capping and polyadenylation have not been well investigated for LTR retrotransposons; Ty1 and copia of Superfamily Copia are translated from capped RNA [32,33] while Idefix of superfamily Gypsy exploits both cap-dependent and independent mechanisms [34]. Retroviruses, which are likely derived from Gypsy retrotransposons [3], produce capped transcripts but appear to exploit both cap-dependent and ‑independent translation [35].…”

Section: Discussionmentioning

confidence: 99%

BARE Retrotransposons Are Translated and Replicated via Distinct RNA Pools

Chang

Jääskeläinen

et al. 2013

PLoS ONE

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The replication of Long Terminal Repeat (LTR) retrotransposons, which can constitute over 80% of higher plant genomes, resembles that of retroviruses. A major question for retrotransposons and retroviruses is how the two conflicting roles of their transcripts, in translation and reverse transcription, are balanced. Here, we show that the BARE retrotransposon, despite its organization into just one open reading frame, produces three distinct classes of transcripts. One is capped, polyadenylated, and translated, but cannot be copied into cDNA. The second is not capped or polyadenylated, but is destined for packaging and ultimate reverse transcription. The third class is capped, polyadenylated, and spliced to favor production of a subgenomic RNA encoding only Gag, the protein forming virus-like particles. Moreover, the BARE2 subfamily, which cannot synthesize Gag and is parasitic on BARE1, does not produce the spliced sub-genomic RNA for translation but does make the replication competent transcripts, which are packaged into BARE1 particles. To our knowledge, this is first demonstration of distinct RNA pools for translation and transcription for any retrotransposon.

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“…These results suggest that only the tap42‐106 defect in Ty1 transcriptional silencing is not upstream of CBC. We have previously shown that plasmids expressing high levels of non‐translatable mRNAs are potent at silencing Ty1 transcription (Wu and Jiang, 2008), and we refer to plasmids such as YEp[LEU2]:Ty1(1–479) and YEp[LEU2]:pPGK1 as ‘super‐initiators’. Importantly, these plasmids fail to silence Ty1 transcription in tap42‐106 cells (Figure 2B).…”

Section: Resultsmentioning

confidence: 99%

“…A number of genetic observations support that both the CBC and the rapamycin‐sensitive TORC1 pathway are involved in mediating Ty1 transcriptional silencing (Wu and Jiang, 2008). First, a non‐lethal concentration of rapamycin eliminates Ty1 transcriptional silencing.…”

Section: Introductionmentioning

confidence: 98%

“…The effects of overproduction of non‐translatable mRNA and the cbc2Δ mutation are not additive, suggesting that they function in the same pathway. We have therefore theorized that high levels of non‐translatable mRNA may functionally inactivate CBC, resulting in a cascade of intracellular signalling that represses Ty1 transcription (Wu and Jiang, 2008). To better understand the role of CBC inactivation in Ty1 transcriptional silencing, we examined the effect of cbc2 Δ on gene expression, using transcriptional microarrays.…”

Section: Introductionmentioning

confidence: 99%

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An essential role of Tap42‐associated PP2A and 2A‐like phosphatases in Ty1 transcriptional silencing of S. cerevisiae

Jiang

2008

Yeast

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We previously reported that overproduction of non-translatable mRNA silences Ty1 transcription, possibly via functional inactivation of the nuclear cap-binding complex (CBC) and subsequent hyperstimulation of the TORC1 pathway. Further experimental evidence for CBC-to-TORC1 signalling in Ty1 transcriptional silencing is presented here. The role of Tap42 (a key downstream component of the TORC1 pathway) was tested. Mutations affecting components of the Tap42-associated PP2A/2A-like phosphatases (Tap42, redundant Pph21/Pph22 and Sit4) eliminate Ty1 transcriptional silencing and epistasis experiments show that the phosphatases function downstream of CBC. Thus, Tap42 functions in the same positive direction as Sit4, Pph21 and Pph22 in Ty1 transcriptional silencing, providing support to the idea that Tap42 may play a positive role in phosphatase activity in response to TORC1 signalling. Moreover, the pph21-102 and sit4-102 mutations affecting interactions of the phosphatases with the Tap42 regulator also abolish Ty1 transcriptional silencing, confirming that the Tap42-phosphatase complex is one required for TORC1-mediated Ty1 transcriptional silencing. PP2A holoenzyme activity, which is independent of Tap42 and TORC1, is not essential for Ty1 transcriptional silencing, strengthening the argument that TORC1-specific signalling underlies Ty1 transcriptional silencing.

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Overproduction of non‐translatable mRNA silences. The transcription of Ty1 retrotransposons in S. cerevisiae via functional inactivation of the nuclear cap‐binding complex and subsequent hyperstimulation of the TORC1 pathway

Cited by 6 publications

References 82 publications

Alternate splicing of transcripts shape macrophage response to Mycobacterium tuberculosis infection

Alternate splicing of transcripts shape macrophage response to Mycobacterium tuberculosis infection

BARE Retrotransposons Are Translated and Replicated via Distinct RNA Pools

An essential role of Tap42‐associated PP2A and 2A‐like phosphatases in Ty1 transcriptional silencing of S. cerevisiae

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