LncRNA–protein interactions: molecular switches for the precise regulation of innate immunity

Abstract

Long non-coding RNAs (lncRNAs) have emerged as important regulators of innate immunity, acting across multiple molecular layers to shape antiviral and inflammatory responses. Among their diverse functions, protein-centered regulation provides a particularly versatile means of controlling immune signaling by altering the functional state, interactions, localization, or turnover of proteins without necessarily changing their transcription. In this review, we synthesize current evidence for lncRNA-mediated protein regulation in innate immunity and propose a protein-centered framework that connects molecular regulatory mechanisms with their functional and immunological consequences. At the mechanistic level, lncRNA–protein interactions can modulate post-translational modifications, alter protein conformations, and facilitate or disrupt protein–protein interactions. These regulatory modes, in turn, affect four major properties of immune proteins: protein stability, subcellular localization, molecular activity, and protein–protein interaction-dependent signal transmission, ultimately reshaping innate immune responses. Across these mechanisms, several recurrent principles emerge, including preferential regulation of functionally important signaling nodes, integration of multiple regulatory mechanisms, and strong dependence on cellular and immunological context. Emerging evidence further suggests that some lncRNAs may act on defined protein states or regulatory interfaces without altering total protein abundance, although the generality of such functional selectivity remains to be established. Together, these findings support a hierarchical model in which lncRNAs translate specific molecular interactions into changes in protein function and, ultimately, innate immune states. This framework provides a basis for understanding how lncRNA–protein interactions contribute to the fine-tuning of innate immunity and for evaluating their potential as targets for selective immune modulation.