July 28th, 2024
Recent Publications Harnessing the Power of Translatomics.
Every week we provide a digest of a small number of recent interesting papers in the field of translatomics.
In this week’s Sunday papers, Ma et al. suggested that targeting N-acetyltransferase 10 could promote heart repair. Shichino et al. stated that eIF4A1 selectively binds to TOP mRNAs to repress the LARP1-mediated translational mechanism during mTORC1 inhibition. Pallarés et al. underlined that the accumulation of Zika virus (ZIKV) non-coding viral RNAs (sfRNAs) block the translation of antiviral genes and triggered PKR activation to produce viral particles.
N-Acetyltransferase 10 represses Uqcr11 and Uqcrb independently of ac4C modification to promote heart regeneration
Nature Communications, 2024
Ma, W., Tian, Y., Shi, L., Liang, J., Ouyang, Q., Li, J., Chen, H., Sun, H., Ji, H., Liu, X. and Huang, W.
N-Acetyltransferase 10 (Nat10) is a significant regulator in cardiac regeneration. It is known primarily for its role in acetylating cytidine residues in RNA (ac4C modification). This study revealed that Nat10 can function independently of its ac4C modification activity.
Using Ribo-seq and RNA-seq, the researchers discovered that genes related to oxidative phosphorylation were translationally downregulated during heart regeneration. Specifically, Nat10 regulated the expression of Uqcr11 and Uqcrb mRNAs in mouse and human cardiomyocytes. Overexpression of Nat10 in cardiomyocytes was found to promote cardiac regeneration and improve cardiac function post-injury. Conversely, inhibiting Nat10 with the pharmacological agent Remodelin or through genetic removal hindered heart regeneration in neonatal mice.
Nat10 suppressed Uqcr11 and Uqcrb independently of its known acetylation activity on cytidine (ac4C). This repression reduced mitochondrial respiration and enhanced the glycolytic capacity of cardiomyocytes, facilitating metabolic reprogramming crucial for regeneration. Nat10 expression was found to be lower in failing female human hearts compared to non-failing ones. This underlined Nat10’s pro-proliferative effects in cardiomyocytes derived from human embryonic stem cells, highlighting its potential as a therapeutic target.
The profiling analysis showed that Nat10 influenced the translation of specific mRNAs related to mitochondrial function, particularly Uqcr11 and Uqcrb. By suppressing these mRNAs, Nat10 reduced mitochondrial respiration while enhancing glycolytic capacity, facilitating a metabolic shift that supports heart regeneration.
Nat10 plays a crucial role in cardiac metabolic reprogramming by controlling the translation of key mitochondrial genes independently of its enzymatic activity associated with ac4C modification. The study highlights Nat10 as an epigenetic regulator of heart regeneration, suggesting that it could be a promising target for clinical therapies aimed at promoting heart repair.
eIF4A1 enhances LARP1-mediated translational repression during mTORC1 inhibition
Nature Structural & Molecular Biology, 2024
Shichino, Y., Yamaguchi, T., Kashiwagi, K., Mito, M., Takahashi, M., Ito, T., Ingolia, N.T., Kuba, K. and Iwasaki, S.
eIF4A1 is a DEAD-box RNA helicase. It plays important role in translation initiation, where it unwinds RNA structures to facilitate ribosome binding. The authors explored the role of eIF4A1 in the translational repression mechanism mediated by La-related protein 1 (LARP1) during the inhibition of the mTORC1 pathway. Unlike its paralog eIF4A2, eIF4A1 selectively bound to terminal oligopyrimidine (TOP) motif-containing mRNAs. This interaction, which was regulated by LARP1, is crucial to repress translation of these mRNAs when mTORC1 activity is inhibited.
Using ribosome profiling, the authors monitored LARP1-mediated translational repression of TOP mRNAs after inhibiting mTOR mechanism. eIF4A1 deletion made TOP mRNAs resistant to mTOR inactivation. This function of eIF4A1 is mediated through its interaction with the RNA-binding protein LARP1, which binds to TOP mRNAs and facilitates their repression when mTORC1 is inhibited. These findings demonstrate that eIF4A1 selectively enhances LARP1’s ability to repress translation of specific mRNAs, highlighting a unique regulatory mechanism within the cellular response to mTORC1 signaling inhibition.
The analysis of polysome profiling showed that the translational repression of endogenous TOP mRNAs, such as RPL10 and RPL13 mRNAs was hampered in EIF4A1-knockout cells. RNA-seq was used to identify the effect of eIF4A1 on the transcriptome of EIF4A1-knockout cells.
The authors demonstrated that eIF4A1 was crucial for LARP1-mediated translational repression of TOP mRNAs during mTORC1 inhibition. This affected the translation of mRNAs involved in cell growth and proliferation. As mTOR inhibitors are promising antitumour drugs, this study highlighted eIF4A1’s role in cancer treatment.
Zika virus non-coding RNAs antagonize antiviral responses by PKR-mediated translational arrest
Nucleic Acids Research, 2024
This study delves into the mechanisms by which the Zika virus (ZIKV) circumvented the host’s antiviral defences. It underlined the role of non-coding viral RNAs, which is known as sfRNAs, produced by ZIKV in evading the host’s immune response. Specifically, the research uncovered how these sfRNAs interfere with the host’s protein kinase R (PKR), a critical component in the antiviral response pathway.
Ribosome profiling was employed to provide a snapshot of active translation by sequencing ribosome-protected mRNA fragments (RPFs). The finding indicated that ZIKV sfRNAs interfered with the host’s protein synthesis machinery.
In general, PKR halts viral replication by phosphorylating the eukaryotic initiation factor 2 alpha (eIF2α), leading to a reduction of protein synthesis. Through ribosome profiling data in ZIKV-infected cells, PKR activation and eIF2α phosphorylation levels were suppressed. It was because ZIKV sfRNAs were found to bind to PKR, and allowed the virus to bypass the translational arrest usually imposed by the host’s immune system, thereby facilitating viral replication.
The profile data also highlighted that in the ZIKV-infected cells, the viral proteins were efficiently translated, although the host protein synthesis was generally suppressed. These findings provide significant insights into ZIKV pathogenesis and reveal potential targets for therapeutic intervention. By elucidating the interaction between ZIKV ncRNAs and PKR, this research opens avenues for developing antiviral strategies aimed at enhancing the host’s innate immune response against Zika virus infection.