bims-protra 2025-08-17 papers

Issue of 2025–08–17
three papers selected by
Marius d’Hervé, McGill University

Proc Natl Acad Sci U S A. 2025 Aug 19. 122(33): e2506281122

ITAF45 is a pervasive trans-acting factor for picornavirus Type II IRES elements.

Michael A Bellucci, Mehdi Amiri, Stephen Berryman, Andia Moshari, Collins Oduor Owino, Rutger D Luteijn, Tobias J Tuthill, Yuri Svitkin, Graham J Belsham, Frank J M van Kuppeveld, Nahum Sonenberg.

Viruses have evolved elaborate mechanisms to hijack the host mRNA translation machinery to direct viral protein synthesis. Picornaviruses, whose RNA genome lacks a cap structure, inhibit cap-dependent mRNA translation, and utilize an internal ribosome entry site (IRES) in the RNA 5' untranslated region to recruit the 40S ribosomal subunit. IRES activity is stimulated by a set of host proteins termed IRES trans-acting factors (ITAFs). The cellular protein ITAF45 (also known as PA2G4 or EBP1) was documented as an essential ITAF for foot-and-mouth disease virus (FMDV), with no apparent role in cell-free systems for encephalomyocarditis virus (EMCV) and Theiler's murine encephalomyelitis virus (TMEV), which are closely related viruses harboring similar IRES elements. Here, we demonstrate that ITAF45 is a pervasive host factor for picornaviruses containing a Type II IRES. CRISPR/Cas9 knockout of ITAF45 in several human cell lines conferred resistance to infection with FMDV, EMCV, TMEV, and equine rhinitis A virus (ERAV). We show that ITAF45 enhances initiation of translation on Type II IRESs in cell line models. This is mediated by the C-terminal lysine-rich region of ITAF45 known to enable binding to viral RNA. These findings challenge previous reports of a restricted role for ITAF45 in FMDV infection, thus positioning ITAF45 as a potential antiviral target for various animal viruses and emerging human cardioviruses.

Keywords: host factor; picornavirus; translation

DOI: https://doi.org/10.1073/pnas.2506281122

bioRxiv. 2025 Jul 14. pii: 2025.07.13.664561. [Epub ahead of print]

The translation initiation factor DHX29 appears to pull on mRNA in a direction opposite to scanning.

Da Cui, Tatyana Pestova, Christopher Hellen, Amedee des Georges.

The DExH-box helicase DHX29 plays a critical role in mammalian translation initiation. It is required for the scanning of mRNAs with complex 5'UTRs. Despite its importance, the detailed mechanism of DHX29's action has remained debated. Using structural models derived from AlphaFold and cryo-EM structure of DHX29 bound to the ribosomal 43S pre-initiation complex, we provide a revised structural framework that clarifies the interplay between DHX29, the 40S ribosomal subunit, and eIF3. Our findings suggest that the 40S subunit regulates DHX29's NTPase activity through an activation mechanism resembling the G-patch protein regulation of DEAH helicases. Moreover, our model supports a 3' to 5' translocase mechanism, in which DHX29 transiently pulls the mRNA opposite to the scanning direction, destabilizing stable stem-loops trapped in the mRNA channel and allowing scanning to resume. This structural analysis refines our understanding of DHX29's function and provides new hypotheses regarding its role in mRNA unwinding during scanning and start codon selection.

DOI: https://doi.org/10.1101/2025.07.13.664561

J Biomol Struct Dyn. 2025 Aug 13. 1-15

Shared regulatory factors influencing mRNA translation rate and half-life in yeast.

Sudipto Basu, Suman Hait, Sudip Kundu.

Extensive research has highlighted the role of codon composition in regulating co-translational mRNA decay. Translational efficiency is often measured using a codon usage metric like the codon adaptation index (CAI), while mRNA stability is assessed through sequence- and structure-dependent metrics such as codon stabilization coefficient and internal unstructured segments (IUS). However, the question remains whether sequence-dependent translation parameters can influence mRNA stability, or if stability-related parameters can, in turn, regulate mRNA translation and overall co-translational decay. Our approach integrates yeast mRNA sequence, structural, and ribosomal density (RD) data to explore the interconnected regulatory determinants that govern mRNA translation and degradation. Our findings offer new insights into how codon preferences and mRNA structuredness impact these processes, with CAI predominantly shaping translation rates and IUS affecting mRNA decay. Additionally, we observe that the impact of RD on co-translational mRNA decay is context-specific, depending on the dynamics of the primary regulators. These primary regulators are conserved across the genome and throughout evolution, emphasizing their importance in maintaining cellular function. We propose that optimizing both CAI and IUS is essential for improving mRNA-based drug delivery systems. A deeper understanding of the relationship between these factors could lead to more effective mRNA therapeutics.

Keywords: Translation rate; codon adaptation index; mRNA half-life; ribosomal density; shared regulators; structuredness

DOI: https://doi.org/10.1080/07391102.2025.2540787