RNA M⁵C MODIFICATION LANDSCAPE: NSUN–TET–YBX/ALYREF AXIS AS A UNIVERSAL REGULATOR OF VIRAL INFECTION AND HOST IMMUNITY

Abstract

RNA 5‑methylcytosine (m⁵C) is a pervasive epitranscriptomic mark that regulates RNA stability, translation, splicing, and nuclear export across coding and noncoding RNAs. A functional axis comprising NSUN methyltransferases (writers), TET dioxygenases (putative editors/oxidizers), and YBX1/ALYREF (readers/export factors) has emerged as a coherent framework to explain how m⁵C dynamically shapes viral infection and host immunity. In this study, we synthesize recent evidence implicating NSUN2/NSUN6 in mRNA and viral RNA methylation, ALYREF in m⁵C‑dependent mRNA export, YBX1 in m⁵C‑dependent RNA stabilization, and TET enzymes in RNA m⁵C oxidation to hm⁵C, with context‑dependent effects on RNA fate and immune visibility.

We conducted a comprehensive literature review of peer‑reviewed studies and multi‑omics resources (2014–2025) across PubMed, Nature Research journals, Frontiers, PLOS, and NAR databases, prioritizing work that maps m⁵C sites, manipulates axis components, and interrogates viral/immune phenotypes. Inclusion emphasized orthogonal validation (e.g., RNA bisulfite‑seq, LC‑MS/MS, CLIP/RIP‑seq), genetic perturbations, and in vivo infection models.

Key findings indicate that NSUN2‑driven m⁵C enhances replication of HBV, HCV, SARS‑CoV‑2, and EV71, often via increased RNA stability/translation and ALYREF‑mediated export; conversely, NSUN2 depletion can heighten type I interferon responses through altered noncoding RNAs and RIG‑I signaling. According to new research, TET2-dependent oxidation of RNA m–C may have implications for antiviral transcriptional programs by modifying chromatin through RNA–protein circuits. Therapeutically, blocking YBX1/ALYREF interactions or modifying NSUN2/TET activity may reduce viral replication or recalibrate immune responses; m²C signatures may function as biomarkers of treatment response or infection severity. 

Conclusively the NSUN–TET–YBX/ALYREF axis is a universal regulator of interactions between viruses and their hosts.. Future work should prioritize standardized m⁵C mapping, time‑resolved infection models, and translational studies to validate targets and optimize intervention strategies.