Evidence of tRNA cleavage in apicomplexan parasites: Half-tRNAs as new potential regulatory molecules of Toxoplasma gondii and Plasmodium berghei

Galizi, Roberto; Spano, Furio; Giubilei, Maria Angela; Capuccini, Barbara; Magini, Alessandro; Urbanelli, Lorena; Ogawa, Tetsuhiro; Dubey, J. P.; Spaccapelo, Roberta; Emiliani, Carla; Cristina, Manlio Di

doi:10.1016/j.molbiopara.2013.03.003

Cited by 22 publications

(26 citation statements)

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“…It is possible, therefore, that the TgPUS1-dependent Ψ's affecting differentiation are found in tRNA(s). If changes in pseudouridylation change expression or processing of tRNAs, tRNA cleavage products that act as regulatory molecules could indirectly affect the cellular pool of mRNAs, producing the changes we observed in TgPUS1-deficient parasites (Phizicky and Hopper 2010;Galizi et al 2013;Hopper 2013).…”

Section: Discussionmentioning

confidence: 89%

mRNA pseudouridylation affects RNA metabolism in the parasite Toxoplasma gondii

Nakamoto

Lovejoy

Cygan

et al. 2017

RNA

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RNA contains over 100 modified nucleotides that are created post-transcriptionally, among which pseudouridine (Ψ) is one of the most abundant. Although it was one of the first modifications discovered, the biological role of this modification is still not fully understood. Recently, we reported that a pseudouridine synthase (TgPUS1) is necessary for differentiation of the singlecelled eukaryotic parasite Toxoplasma gondii from active to chronic infection. To better understand the biological role of pseudouridylation, we report here gel-based and deep-sequencing methods to identify TgPUS1-dependent Ψ's in Toxoplasma RNA, and the use of TgPUS1 mutants to examine the effect of this modification on mRNAs. In addition to identifying conserved sites of pseudouridylation in Toxoplasma rRNA, tRNA, and snRNA, we also report extensive pseudouridylation of Toxoplasma mRNAs, with the Ψ's being relatively depleted in the 3 ′ ′ ′ ′ ′ -UTR but enriched at position 1 of codons. We show that many Ψ's in tRNA and mRNA are dependent on the action of TgPUS1 and that TgPUS1-dependent mRNA Ψ's are enriched in developmentally regulated transcripts. RNA-seq data obtained from wild-type and TgPUS1-mutant parasites shows that genes containing a TgPUS1-dependent Ψ are relatively more abundant in mutant parasites, while pulse/chase labeling of RNA with 4-thiouracil shows that mRNAs containing TgPUS1-dependent Ψ have a modest but statistically significant increase in half-life in the mutant parasites. These data are some of the first evidence suggesting that mRNA Ψ's play an important biological role.

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Section: Discussionmentioning

confidence: 89%

mRNA pseudouridylation affects RNA metabolism in the parasite Toxoplasma gondii

Nakamoto

Lovejoy

Cygan

et al. 2017

RNA

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“…It was observed that avirulent isolates of T. gondii and attenuated P. berghei parasites displayed higher rates of tRNA cleavage compared to virulent strains. Also tRNA half production was significantly higher in the metabolically quiescent bradyzoite and sporozoite stages of T. gondii , compared to the fast-growing tachyzoite indicating a relationship between half-tRNA production and growth rate in this important group of organisms (Galizi et al, 2013). A role for tRF halves in Respiratory Syncytial Virus (RSV) infectivity was recently shown by Wang et al who observed an induction of tRNA cleavage upon RSV infection with a specific subset of tRNAs being cleaved.…”

Section: Trna-derived Fragmentsmentioning

confidence: 99%

tRNAs as regulators of biological processes

Raina¹,

Ibba²

2014

Front. Genet.

283

263

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Transfer RNAs (tRNA) are best known for their role as adaptors during translation of the genetic code. Beyond their canonical role during protein biosynthesis, tRNAs also perform additional functions in both prokaryotes and eukaryotes for example in regulating gene expression. Aminoacylated tRNAs have also been implicated as substrates for non-ribosomal peptide bond formation, post-translational protein labeling, modification of phospholipids in the cell membrane, and antibiotic biosyntheses. Most recently tRNA fragments, or tRFs, have also been recognized to play regulatory roles. Here, we examine in more detail some of the new functions emerging for tRNA in a variety of cellular processes outside of protein synthesis.

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“…However, the lack of half-exon 15 results in a transcript coding for a tRNaseZ devoid of a key domain essential for the enzyme function. As for the second tRNaseZ gene, named TgTM-tRNaseZ (Galizi et al 2013), we detected only one alternative form along with the predicted fully spliced transcript (Fig. 1b).…”

Section: Does Intron Retention Regulate Gene Expression In Parasites?mentioning

confidence: 94%

“…In work published in 2013 (Galizi et al 2013), we described a new phenomenon occurring in T. gondii and Plasmodium berghei consisting on production of halftRNAs in response to several stimuli, such as starvation, and during parasite differentiation. Although we have not investigated the role of these molecules in parasites, halftRNAs in other organisms have been shown to bind target messengers and drive cleavage of these transcripts by tRNaseZ (Haussecker et al 2010).…”

Section: Does Intron Retention Regulate Gene Expression In Parasites?mentioning

confidence: 99%

“…Although we have not investigated the role of these molecules in parasites, halftRNAs in other organisms have been shown to bind target messengers and drive cleavage of these transcripts by tRNaseZ (Haussecker et al 2010). We have identified two putative tRNaseZs in both T. gondii and Plasmodium species (Galizi et al 2013) and hypothesized that these proteins may work in concert with half-tRNAs to regulate gene expression. Unpublished results aimed at characterizing the expression of T. gondii tRNaseZ genes showed the existence of alternative transcripts derived by use of different splicing donor sites.…”

Section: Does Intron Retention Regulate Gene Expression In Parasites?mentioning

confidence: 99%

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Alternative splicing mechanisms orchestrating post-transcriptional gene expression: intron retention and the intron-rich genome of apicomplexan parasites

et al. 2015

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Apicomplexan parasites including Toxoplasma gondii and Plasmodium species have complex life cycles that include multiple hosts and differentiation through several morphologically distinct stages requiring marked changes in gene expression. This review highlights emerging evidence implicating regulation of mRNA splicing as a mechanism to prime these parasites for rapid gene expression upon differentiation. We summarize the most important insights in alternative splicing including its role in regulating gene expression by decreasing mRNA abundance via 'Regulated Unproductive Splicing and Translation'. As a related but less well-understood mechanism, we discuss also our recent work suggesting a role for intron retention for precluding translation of stage specific isoforms of T. gondii glycolytic enzymes. We additionally provide new evidence that intron retention might be a widespread mechanism during parasite differentiation. Supporting this notion, recent genome-wide analysis of Toxoplasma and Plasmodium suggests intron retention is more pervasive than heretofore thought. These findings parallel recent emergence of intron retention being more prevalent in mammals than previously believed, thereby adding to the established roles in plants, fungi and unicellular eukaryotes. Deeper mechanistic studies of intron retention will provide important insight into its role in regulating gene expression in apicomplexan parasites and more general in eukaryotic organisms.

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Evidence of tRNA cleavage in apicomplexan parasites: Half-tRNAs as new potential regulatory molecules of Toxoplasma gondii and Plasmodium berghei

Cited by 22 publications

References 50 publications

mRNA pseudouridylation affects RNA metabolism in the parasite Toxoplasma gondii

mRNA pseudouridylation affects RNA metabolism in the parasite Toxoplasma gondii

tRNAs as regulators of biological processes

Alternative splicing mechanisms orchestrating post-transcriptional gene expression: intron retention and the intron-rich genome of apicomplexan parasites

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