Biology subjects

Wacquiez, A.

Publications and source records attributed to Wacquiez, A..

3 recordsLinked to original sources

bioRxiv2026

eIF4E3 drives translation of viral mRNAs with short 5' UTRs

Eukaryotic cells express three paralogs of the cap-binding protein eIF4E, yet the functions of the less-studied family members remain poorly understood. Here we demonstrate that eIF4E3, a paralog whose expression is tissue-restricted and whose activity is insensitive to inhibition by eIF4E-binding proteins (4EBPs), drives efficient translation of viral mRNAs with short 5 untranslated regions (UTRs). Many negative-strand RNA viruses (NSVs), including vesicular stomatitis virus (VSV), respiratory syncytial virus (RSV), and influenza A virus (IAV), produce mRNAs with extremely short 5UTRs that are incompatible with canonical cap-dependent scanning translation initiation. Using an auxin-inducible degron (AID) system to acutely deplete endogenous eukaryotic initiation factors during active viral infection, we demonstrate that translation of these short-UTR viral mRNAs occurs independently of eIF4E1, the canonical cap-binding protein, while remaining dependent on eIF4E3. In contrast, Ebola virus (EBOV), whose mRNAs bear long, structured 5UTRs, remains eIF4E1-dependent, implicating 5UTR length and structural complexity as cis determinants of eIF4E paralog selectivity. During VSV infection, 4EBP dephosphorylation sequesters eIF4E1 and broadly suppresses host cap-dependent translation. Because eIF4E3 escapes 4EBP-mediated regulation and preferentially engages short, unstructured 5UTRs, it is uniquely positioned to sustain viral protein synthesis under these conditions. These findings reveal that VSV exploits a cellular paralog-switching mechanism by co-opting eIF4E3 to maintain viral translation when canonical eIF4F activity is suppressed and establish eIF4E3 as a proviral factor whose tissue-restricted expression in the lung may influence susceptibility to clinically important respiratory pathogens.

molecular biology↗

bioRxiv2026

The enteroviral protease target LSM14A operates outside of P-bodies to augment antiviral innate immunity

Antiviral innate immune networks in human cells comprise core components that serve as central signaling hubs and several context-dependent modulators whose role may be virus- or tissue-specific. One such modulator is LSM14A, which potentiates innate immune response but is not essential. We recently showed that enteroviruses deploy their protease activity to cleave LSM14A, thereby disabling its antiviral function. In this study, we probe the molecular mechanism by which LSM14A contributes to innate immunity. We show that although LSM14A predominantly localizes to processing bodies (P-bodies; PBs), this localization is not essential for its innate immune function. Likewise, association with peroxisomes does not contribute to its immune activity. Instead, an unbiased systems-level interactomic analysis reveals a distinct cohort of LSM14A-associated proteins that assemble outside canonical PBs and peroxisomes following infection with Sendai virus, a robust inducer of innate immunity. Functional interrogation of these interactors demonstrate that several are essential for LSM14A-dependent amplification of antiviral signaling. Together, these findings uncover a functional axis of LSM14A that operates independently of its canonical subcellular localizations and is mediated through a specialized interaction network, improving our understanding of how this protein reinforces the antiviral innate immune system.

microbiology↗

bioRxiv2025

Cis-aconitate therapy protects against influenza mortality by dual targeting of viral polymerase and ERK/AKT/NF-κB signaling

Influenza virus poses a significant global health challenge, causing approximately 500,000 deaths annually. Its ability to evade antiviral treatments and vaccine-induced immunity underscores the need for novel therapeutic approaches. Our study identifies cis-aconitate (cis-aco), a mitochondria-derived metabolite, as a potent dual-action agent against influenza, independently of its metabolic derivative, itaconate. Cis-aco impairs viral polymerase activity, suppressing viral mRNA expression and protein synthesis to inhibit replication across a range of influenza subtypes. This antiviral efficacy is confirmed in ex vivo human airway and lung organotypic models. Beyond its antiviral properties, cis-aco exhibits potent anti-inflammatory effects, disrupting key inflammatory cascades and reducing the secretion of inflammatory mediators. In a mouse model of influenza pneumonia, cis-aco mitigates viral replication, inflammation, and immune cell activation, significantly improving survival. Notably, its efficacy persists even when administered at later stages of infection, when oseltamivir/Tamiflu(R) is no longer effective. These findings position cis-aco as a promising influenza treatment, combining antiviral and anti-inflammatory benefits within a clinically relevant timeframe.

immunology↗