Viroid-Derived siRNAs: Minimal RNAs Driving Multiscale Perturbations of Host Regulatory Systems.

Abstract

Viroids are the simplest known infectious agents, consisting of noncoding circular RNAs that replicate autonomously in plant hosts while inducing profound and systemic alterations in host biology. This apparent paradox positions viroids as powerful models for understanding how RNA molecules encode biological information independently of protein translation. A hallmark of viroid infection is the production of viroid-derived small interfering RNAs (vd-siRNAs) by the host RNA silencing machinery. Here, we propose that vd-siRNAs function not merely as antiviroid byproducts, but as active effectors that translate RNA structural information into gene regulatory activity. Through sequence complementarity and selective incorporation into Argonaute complexes, vd-siRNAs influence host gene expression at multiple levels, including transcript abundance, protein accumulation, epigenetic states, and metabolic pathways. Importantly, their effects extend beyond individual targets and are consistent with broader perturbations of interconnected host regulatory networks, potentially contributing to coordinated transcriptional reprogramming and disease-associated phenotypes. By integrating molecular, transcriptomic, epigenetic, and systems-level evidence, we propose a "structure-to-network" perspective in which viroid RNAs function as minimal informational systems capable of interfacing with complex cellular pathways. Within this context, vd-siRNAs emerge as mechanistic links between RNA architecture and multiscale biological responses. Finally, we discuss how this framework expands our understanding of RNA-mediated regulation and highlights the broader regulatory potential of structured noncoding RNAs.