Work

SEC11A identified as a critical host factor for HMPV through virus-induced alternative splicing

Year: 2026

Type: article

Abstract: • Scientific question: This study aims to systematically identify host factors that influence human metapneumovirus (HMPV) replication through virus-induced alternative splicing (AS) events, and to determine whether such splicing-mediated mechanisms exhibit virus-specific characteristics. The central goal is to uncover novel host-dependent regulatory pathways that may serve as potential targets for antiviral strategies. • Evidence before this study: Previous research has established that numerous viruses manipulate host RNA splicing to enhance their replication or evade immune responses. Studies on flaviviruses and influenza viruses have identified viral proteins that interact with splicing machinery. However, a systematic understanding of how HMPV – a significant pediatric respiratory pathogen – reshapes the host splicing landscape, and which resulting splicing events are functionally important for infection, remained largely unexplored. • New findings: We globally characterized HMPV-induced alternative splicing in human lung epithelial cells (BEAS-2B) using RNA-Seq. Functional validation revealed that the SEC11A gene, a subunit of the signal peptidase complex, is a crucial host factor for HMPV replication. Its loss significantly impaired viral production. Importantly, the specific splicing pattern of SEC11A observed during HMPV infection was not seen with other common respiratory viruses, indicating a virus-specific mechanism. • Significance of the study: This work establishes SEC11A as the HMPV-specific host dependency factor identified through a splicing-centric approach, highlighting viral manipulation of the host secretory pathway. It provides a novel conceptual framework for understanding pneumovirus–host interactions and positions SEC11A as a compelling candidate for the development of host-directed antivirals against HMPV. Alternative splicing (AS) significantly expands the diversity of the eukaryotic proteome, and virus-induced alterations in AS have emerged as a novel paradigm for studying virus-host interactions. Human metapneumovirus (HMPV) engages with host cells through multiple mechanisms, directly or indirectly utilizing various host systems to facilitate its infection and replication. In this study, the human normal lung epithelial cell line BEAS-2B was used as the cell model for HMPV infection. Then, the host gene alternative splicing events upon HMPV infection was globally characterized by RNA-Seq. Selected alternative splicing events were confirmed, and their associated genes were evaluated for effects on HMPV replication in knockout cell lines. Among these, HMPV replication was greatly reduced in SEC11A gene deletion cells, suggesting the SEC11A gene is a critical host factor for HMPV infection. Notably, this splicing pattern of SEC11A gene was not changed during infection with other respiratory viruses. In summary, this study provides new insights into HMPV pathogenesis, and lays a crucial foundation for further exploration of HMPV-host interactions and the development of potential host-directed antiviral therapeutics

Source: Biosafety and Health

DOI: 10.1016/j.bsheal.2026.01.001