BIK polymorphism and proteasome regulation unveil host risk factor for severe influenza

• 成果类型: Article
• 署名作者: Soni, Sourabh; Yildiz, Soner; Allen, Emma Kaitlynn; Petersen, Hans; Peeples, Mark; El Zahed, Sara; Rosas, Lorena; Anang, Vandana; Antonescu, Laura; Nho, Richard Seonghun; Mora, Ana Lucia; Horowitz, Jeffrey Craig; Rojas, Mauricio; Medina, Rafael Andres; Thomas, Paul Glyndwr; Garcia-Sastre, Adolfo; Tesfaigzi, Yohannes; Mebratu, Yohannes Afework
• 署名单位: University System of Ohio; Ohio State University; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; St Jude Children's Research Hospital; Lovelace Respiratory Research Institute; University System of Ohio; Ohio State University; Nationwide Childrens Hospital; Research Institute at Nationwide Children's Hospital; Center for Vaccines & Immunity; Emory University; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Brigham & Women's Hospital
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15003
• DOI: 10.1073/pnas.2424367122
• 发表日期: 2025-07-15
• 关键词: virus nucleoprotein; induced-apoptosis; adamantane resistance; h5n1 influenza; bcl-2 family; protein; expression; interacts; binding; IMPACT

摘要

Influenza A viruses (IAVs) pose a significant public health threat, with host factors playing a crucial role in disease severity. We investigated the role of Bcl-2-interacting killer (BIK) in IAV infection using cellular and mouse models, and influenza-infected human cohort. In airway epithelial cells (AECs), BIK deficiency impaired viral replication, while BIK restoration enhanced it. Conversely, airway-specific BIK overexpression in mice increased viral load, inflammation, and mortality, whereas BIK suppression conferred protection. Critically, a genetic variation (rs738276) in the BIKgene, influencing BIK expression, correlates with altered viral replication in air-liquid interface differentiated primary normal human bronchial epithelial cells and influenza severity in humans. Mechanistically, we demonstrate that IAV nucleoprotein (NP) suppresses beta 5, a subunit of the proteasome, leading to increased BIK levels and enhanced viral replication. Conversely, beta 5 treatment dampened BIK levels and protected mice from IAV-induced morbidity and mortality. Furthermore, BIK interacts with NP, disrupting the Bcl-2/NP interaction and promoting viral replication. Our findings uncover an IAV-BIK-beta 5 axis that governs viral replication, suggesting that targeting BIK or beta 5 may offer therapeutic strategies against influenza.