Cristian Prieto-Garcia | PubMed Health

PubMed2026

Programmed ribosomal frameshifting triggers translational stress to promote viral replication.

Programmed ribosomal frameshifting (PRF) is a conserved viral strategy for expressing polyproteins from compact genomes. Although PRF is traditionally viewed as a structural mechanism, here we show that it functions as a regulatory signal that rewires host translation in favor of viral replication. A minimal SARS-CoV-2 PRF element is sufficient to activate the GCN2 arm of the integrated stress response (ISR) independently of the canonical ISR sensor ZAKα. This activation serves as a temporal switch during early infection to shut off host translation and is required for viral propagation in cells and human airway organoids. Proteomic and genetic screens identify DRG1 and IGF2BP3 as key mediators of PRF-induced GCN2 activation. We further show that this PRF-GCN2 axis is conserved in human immunodeficiency virus (HIV)-1 and West Nile virus, highlighting its broad relevance across RNA viruses. These findings reveal a sophisticated mechanism of viral translational control, highlighting PRF as a stress-inducing module that enhances viral replication.

RNA virus↗

PubMed2025

A novel feedback loop between DYRK2 and USP28 regulates cancer homeostasis and DNA damage signaling.

Posttranslational modifications, such as ubiquitination and phosphorylation, play pivotal roles in regulating protein stability in response to cellular stress. Dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) and ubiquitin-specific peptidase 28 (USP28) are critical regulators of cell cycle progression, DNA damage response, and oncogenic signaling. However, their functional interplay remains largely unexplored. Here, we describe a novel bidirectional regulatory mechanism between DYRK2 and USP28 that integrates DNA damage response and ubiquitin-mediated protein degradation. We demonstrate that DYRK2 phosphorylates USP28, promoting its ubiquitination and proteasomal degradation in a kinase activity-independent manner, thereby contributing to the maintenance of oncogenic protein homeostasis. Conversely, USP28 functions as a deubiquitinase for DYRK2, stabilizing its protein levels and enhancing its kinase activity. Notably, we show that DYRK2 interacts and co-localizes with USP28, with the 521-541 DYRK2 region, particularly residue T525, playing a crucial role in USP28-mediated DYRK2 stabilization. Functionally, this reciprocal regulation modulates p53 signaling, influencing apoptotic responses to DNA damage. DYRK2-mediated phosphorylation of p53 at S46 is significantly reduced upon USP28 depletion, suggesting that USP28 facilitates DYRK2-dependent apoptosis. Additionally, our results highlight a complex regulatory axis involving USP28 and DYRK2, with implications for oncogenic cell death and genomic stability. Overall, our findings uncover a novel feedback loop in which DYRK2 and USP28 dynamically regulate each other to control proto-oncoprotein homeostasis and DNA damage signaling. This interplay offers potential therapeutic opportunities for targeting cancers with dysregulated ubiquitination and genomic instability.

Dyrk Kinases↗