tRNA renovatio: Rebirth through fragmentation

Kuhle, Bernhard; Chen, Qi; Schimmel, Paul

doi:10.1016/j.molcel.2023.09.016

Cited by 32 publications

(11 citation statements)

References 209 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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“…Regulatory RNAs can be expressed from IGRs, as well as from the 5′- and 3′UTRs of mRNAs, and the CDS ( 79 ). In addition, RNA regulators can also originate from stable transcripts, such as tRNAs ( 80 , 81 ). Therefore, the identification of base-pairing regulators from the pool of all cellular transcripts can be difficult based on standard transcriptome data.…”

Section: Discussionmentioning

confidence: 99%

ChimericFragments: computation, analysis and visualization of global RNA networks

Siemers,

Lippegaus,

Papenfort

2024

NAR Genomics and Bioinformatics

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RNA–RNA interactions are a key feature of post-transcriptional gene regulation in all domains of life. While ever more experimental protocols are being developed to study RNA duplex formation on a genome-wide scale, computational methods for the analysis and interpretation of the underlying data are lagging behind. Here, we present ChimericFragments, an analysis framework for RNA-seq experiments that produce chimeric RNA molecules. ChimericFragments implements a novel statistical method based on the complementarity of the base-pairing RNAs around their ligation site and provides an interactive graph-based visualization for data exploration and interpretation. ChimericFragments detects true RNA–RNA interactions with high precision and is compatible with several widely used experimental procedures such as RIL-seq, LIGR-seq or CLASH. We further demonstrate that ChimericFragments enables the systematic detection of novel RNA regulators and RNA–target pairs with crucial roles in microbial physiology and virulence. ChimericFragments is written in Julia and available at: https://github.com/maltesie/ChimericFragments.

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“…(3) Deep-sequencing technology can assist with tsRNA detection. Some researchers have proposed that the development of artificial intelligence (AI), machine learning, and microfluidic biochip technology will enhance our ability to identify tsRNAs involved in tumor diagnosis [ 186 , 187 ]. For example, artificial neural networks are used to integrate multiple layers of tsRNA information (e.g., biogenesis, site-specific RNA modifications, and expression levels), which will help identify potential biomarkers for tumor diagnosis [ 9 , 188 ].…”

Section: Discussion and Future Perspectivesmentioning

confidence: 99%

tRNA-derived small RNAs in human cancers: roles, mechanisms, and clinical application

Zhou,

He,

Zhang

et al. 2024

Mol Cancer

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Transfer RNA (tRNA)-derived small RNAs (tsRNAs) are a new type of non-coding RNAs (ncRNAs) produced by the specific cleavage of precursor or mature tRNAs. tsRNAs are involved in various basic biological processes such as epigenetic, transcriptional, post-transcriptional, and translation regulation, thereby affecting the occurrence and development of various human diseases, including cancers. Recent studies have shown that tsRNAs play an important role in tumorigenesis by regulating biological behaviors such as malignant proliferation, invasion and metastasis, angiogenesis, immune response, tumor resistance, and tumor metabolism reprogramming. These may be new potential targets for tumor treatment. Furthermore, tsRNAs can exist abundantly and stably in various bodily fluids (e.g., blood, serum, and urine) in the form of free or encapsulated extracellular vesicles, thereby affecting intercellular communication in the tumor microenvironment (TME). Meanwhile, their abnormal expression is closely related to the clinicopathological features of tumor patients, such as tumor staging, lymph node metastasis, and poor prognosis of tumor patients; thus, tsRNAs can be served as a novel type of liquid biopsy biomarker. This review summarizes the discovery, production, and expression of tsRNAs and analyzes their molecular mechanisms in tumor development and potential applications in tumor therapy, which may provide new strategies for early diagnosis and targeted therapy of tumors.

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tRNA renovatio: Rebirth through fragmentation

Cited by 32 publications

References 209 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

ChimericFragments: computation, analysis and visualization of global RNA networks

tRNA-derived small RNAs in human cancers: roles, mechanisms, and clinical application

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tRNA renovatio: Rebirth through fragmentation

Cited by 32 publications

References 209 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

ChimericFragments: computation, analysis and visualization of global RNA networks

tRNA-derived small RNAs in human cancers: roles, mechanisms, and clinical application

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Product

Resources

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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