Emerging functional principles of tRNA-derived small RNAs and other regulatory small RNAs

Chen, Qi; Zhou, Tong

doi:10.1016/j.jbc.2023.105225

Cited by 13 publications

(4 citation statements)

References 180 publications

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“…The activity of the 5′-tRNA ValCAC/AAC half was stronger than that of GUUU repeats of the same length, suggesting that beyond the GUUU motif, there are other, yet unidentified molecular factors within the 5′-tRNA ValCAC/AAC half, such as secondary or tertiary structures, that facilitate endosomal enzymatic cleavage and/or TLR7 binding. In light of this, the roles of secondary and tertiary structures of tRNA-derived sncRNAs across various biological processes have been discussed in recent reviews ( 79 , 80 ).…”

Section: Discussionmentioning

confidence: 99%

The tRNA ^Val half: A strong endogenous Toll-like receptor 7 ligand with a 5′-terminal universal sequence signature

Pawar,

Kawamura,

Kirino

2024

Proc. Natl. Acad. Sci. U.S.A.

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Toll-like receptors (TLRs) are crucial components of the innate immune system. Endosomal TLR7 recognizes single-stranded RNAs, yet its endogenous ssRNA ligands are not fully understood. We previously showed that extracellular (ex-) 5′-half molecules of tRNA HisGUG (the 5′-tRNA HisGUG half) in extracellular vesicles (EVs) of human macrophages activate TLR7 when delivered into endosomes of recipient macrophages. Here, we fully explored immunostimulatory ex-5′-tRNA half molecules and identified the 5′-tRNA ValCAC/AAC half, the most abundant tRNA-derived RNA in macrophage EVs, as another 5′-tRNA half molecule with strong TLR7 activation capacity. Levels of the ex-5′-tRNA ValCAC/AAC half were highly up-regulated in macrophage EVs upon exposure to lipopolysaccharide and in the plasma of patients infected with Mycobacterium tuberculosis . The 5′-tRNA ValCAC/AAC half-mediated activation of TLR7 effectively eradicated bacteria infected in macrophages. Mutation analyses of the 5′-tRNA ValCAC/AAC half identified the terminal GUUU sequence as a determinant for TLR7 activation. We confirmed that GUUU is the optimal ratio of guanosine and uridine for TLR7 activation; microRNAs or other RNAs with the terminal GUUU motif can indeed stimulate TLR7, establishing the motif as a universal signature for TLR7 activation. These results advance our understanding of endogenous ssRNA ligands of TLR7 and offer insights into diverse TLR7-involved pathologies and their therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

The tRNA ^Val half: A strong endogenous Toll-like receptor 7 ligand with a 5′-terminal universal sequence signature

Pawar,

Kawamura,

Kirino

2024

Proc. Natl. Acad. Sci. U.S.A.

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“…Therefore, the conventional sRNA-seq method employed in this study may have limitations in detecting functional sRNAs. Furthermore, this study primarily focuses on linear complementarity-based mechanisms of sRNAs; however, recent research suggests that tsRNAs or rsRNAs may exert their functions through 3D structures 29 . Hence, further investigation is required to elucidate the role of RNA in epigenetics.…”

Section: Discussionmentioning

confidence: 99%

Inter- and trans-generational impacts of real-world PM2.5 exposure on male-specific primary hypogonadism

Wei,

Zhang,

et al. 2024

Cell Discov

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Exposure to PM2.5, a harmful type of air pollution, has been associated with compromised male reproductive health; however, it remains unclear whether such exposure can elicit transgenerational effects on male fertility. Here, we aim to examine the effect of paternal exposure to real-world PM2.5 on the reproductive health of male offspring. We have observed that paternal exposure to real-world PM2.5 can lead to transgenerational primary hypogonadism in a sex-selective manner, and we have also confirmed this phenotype by using an external model. Mechanically, we have identified small RNAs (sRNAs) that play a critical role in mediating these transgenerational effects. Specifically, miR6240 and piR016061, which are present in F0 PM sperm, regulate intergenerational transmission by targeting Lhcgr and Nsd1, respectively. We have also uncovered that piR033435 and piR006695 indirectly regulate F1 PM sperm methylation by binding to the 3′-untranslated region of Tet1 mRNA. The reduced expression of Tet1 resulted in hypermethylation of several testosterone synthesis genes, including Lhcgr and Gnas, impaired Leydig cell function and ultimately led to transgenerational primary hypogonadism. Our findings provide insights into the mechanisms underlying the transgenerational effects of paternal PM2.5 exposure on reproductive health, highlighting the crucial role played by sRNAs in mediating these effects. The findings underscore the significance of paternal pre-conception interventions in alleviating the adverse effects of environmental pollutants on reproductive health.

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“…The expectation that methodological improvements will unveil new biological features and basic principles is embodied in the article by Chen and Zhou ( 4 ), who summarize the growing inventory of small non-coding RNAs (sncRNAs), including those derived from tRNAs. Prevalent RNA modifications ( e.g.…”

mentioning

confidence: 99%

“…, PANDORA-seq) have led to the discovery of a vast number of sncRNAs in different cells/tissues. In addition to a description of the existence of a broader sncRNA-centered regulatory RNA landscape that extends far beyond RNAi, Chen and Zhou ( 4 ) articulate the hypothesis that many of these sncRNAs function in an aptamer-like fashion and that their ubiquity in all domains of life (unlike RNAi) represent a more ancient mechanism that ultimately paved the path to RNAi. Regardless of this postulated evolutionary trajectory, reports of new sncRNA-mediated mechanisms for controlling gene expression and even protein function attest to the pervasive roles of RNAs as master regulators, a possible legacy from the RNA world.…”

mentioning

confidence: 99%

Transfer RNAs: A treasure trove that keeps on giving

Gopalan,

Musier-Forsyth

2023

Journal of Biological Chemistry

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Emerging functional principles of tRNA-derived small RNAs and other regulatory small RNAs

Cited by 13 publications

References 180 publications

The tRNA ^Val half: A strong endogenous Toll-like receptor 7 ligand with a 5′-terminal universal sequence signature

The tRNA ^Val half: A strong endogenous Toll-like receptor 7 ligand with a 5′-terminal universal sequence signature

Inter- and trans-generational impacts of real-world PM2.5 exposure on male-specific primary hypogonadism

Transfer RNAs: A treasure trove that keeps on giving

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Emerging functional principles of tRNA-derived small RNAs and other regulatory small RNAs

Cited by 13 publications

References 180 publications

The tRNA Val half: A strong endogenous Toll-like receptor 7 ligand with a 5′-terminal universal sequence signature

The tRNA Val half: A strong endogenous Toll-like receptor 7 ligand with a 5′-terminal universal sequence signature

Inter- and trans-generational impacts of real-world PM2.5 exposure on male-specific primary hypogonadism

Transfer RNAs: A treasure trove that keeps on giving

Contact Info

Product

Resources

About

The tRNA ^Val half: A strong endogenous Toll-like receptor 7 ligand with a 5′-terminal universal sequence signature

The tRNA ^Val half: A strong endogenous Toll-like receptor 7 ligand with a 5′-terminal universal sequence signature