Ubiquitin-Dependent Regulation of Influenza A Virus Polymerase and vRNP Function: Mechanisms and Therapeutic Opportunities

Abstract

Influenza A virus (IAV) remains a major threat to global public health because of its capacity for antigenic drift, reassortment, zoonotic transmission, and pandemic emergence. Viral transcription and genome replication are carried out by the influenza virus RNA-dependent RNA polymerase (FluPol), a heterotrimeric complex composed of polymerase basic protein 1 (PB1), polymerase basic protein 2 (PB2), and polymerase acidic protein (PA), which functions together with nucleoprotein (NP) within viral ribonucleoprotein complexes (vRNPs). FluPol activity is regulated not only by viral determinants and host cofactors but also by diverse post-translational modifications. Among these, ubiquitination has emerged as a particularly versatile regulatory mechanism because it can control protein stability, polymerase assembly, subunit interactions, conformational dynamics, NP–RNA interactions, and innate immune signaling. Depending on the modified substrate, ubiquitin linkage type, acceptor residue, and responsible E3 ligase or deubiquitinase, ubiquitination may either restrict IAV replication or be exploited by the virus to enhance polymerase function and vRNP activity. This review summarizes recent advances in ubiquitination-mediated regulation of FluPol and NP, focusing on the responsible E3 ubiquitin ligases, deubiquitinases, ubiquitination sites, ubiquitin-chain types, and host restriction mechanisms. We further discuss the crosstalk between ubiquitination and other post-translational modifications, highlight unresolved mechanistic questions, and evaluate the therapeutic potential and challenges of targeting ubiquitin-dependent pathways for antiviral intervention. Collectively, this review provides a conceptual framework for understanding how ubiquitination shapes IAV replication and identifies E3 ligases and DUBs as potential targets for host-directed antiviral strategies.