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

• 成果类型: Article
• 署名作者: Bellucci, Michael A.; Amiri, Mehdi; Berryman, Stephen; Moshari, Andia; Owino, Collins Oduor; Luteijn, Rutger D.; Tuthill, Tobias J.; Svitkin, Yuri; Belsham, Graham J.; van Kuppeveld, Frank J. M.; Sonenberg, Nahum
• 署名单位: McGill University; McGill University; UK Research & Innovation (UKRI); Biotechnology and Biological Sciences Research Council (BBSRC); Pirbright Institute; Utrecht University; University of Copenhagen
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11447
• DOI: 10.1073/pnas.2506281122
• 发表日期: 2025-08-19
• 关键词: encephalomyocarditis virus; translation initiation; mouth-disease; internal initiation; cardiovirus rnas; messenger-rna; protein; sequence; binding; ebp1

摘要

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.