tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A
. 2025 Jul 15;122(28):e2424367122.
doi: 10.1073/pnas.2424367122. Epub 2025 Jul 8. BIK polymorphism and proteasome regulation unveil host risk factor for severe influenza
Sourabh Soni[SUP] 1 [/SUP], Soner Yildiz[SUP] 2 3 [/SUP], Emma Kaitlynn Allen[SUP] 4 [/SUP], Hans Petersen[SUP] 5 [/SUP], Mark Peeples[SUP] 6 [/SUP], Sara El Zahed[SUP] 2 3 [/SUP], Lorena Rosas[SUP] 1 [/SUP], Vandana Anang[SUP] 1 [/SUP], Laura Antonescu[SUP] 1 [/SUP], Richard Seonghun Nho[SUP] 1 [/SUP], Ana Lucia Mora[SUP] 1 [/SUP], Jeffrey Craig Horowitz[SUP] 1 [/SUP], Mauricio Rojas[SUP] 1 [/SUP], Rafael Andrés Medina[SUP] 7 [/SUP], Paul Glyndwr Thomas[SUP] 4 [/SUP], Adolfo García-Sastre[SUP] 2 3 8 9 10 11 [/SUP], Yohannes Tesfaigzi[SUP] 12 [/SUP], Yohannes Afework Mebratu[SUP] 1 [/SUP]
Affiliations
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 BIK gene, 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 β5, a subunit of the proteasome, leading to increased BIK levels and enhanced viral replication. Conversely, β5 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-β5 axis that governs viral replication, suggesting that targeting BIK or β5 may offer therapeutic strategies against influenza.
Keywords: BIK; Beta 5; Influenza A virus; Proteasome; SNP.
. 2025 Jul 15;122(28):e2424367122.
doi: 10.1073/pnas.2424367122. Epub 2025 Jul 8. BIK polymorphism and proteasome regulation unveil host risk factor for severe influenza
Sourabh Soni[SUP] 1 [/SUP], Soner Yildiz[SUP] 2 3 [/SUP], Emma Kaitlynn Allen[SUP] 4 [/SUP], Hans Petersen[SUP] 5 [/SUP], Mark Peeples[SUP] 6 [/SUP], Sara El Zahed[SUP] 2 3 [/SUP], Lorena Rosas[SUP] 1 [/SUP], Vandana Anang[SUP] 1 [/SUP], Laura Antonescu[SUP] 1 [/SUP], Richard Seonghun Nho[SUP] 1 [/SUP], Ana Lucia Mora[SUP] 1 [/SUP], Jeffrey Craig Horowitz[SUP] 1 [/SUP], Mauricio Rojas[SUP] 1 [/SUP], Rafael Andrés Medina[SUP] 7 [/SUP], Paul Glyndwr Thomas[SUP] 4 [/SUP], Adolfo García-Sastre[SUP] 2 3 8 9 10 11 [/SUP], Yohannes Tesfaigzi[SUP] 12 [/SUP], Yohannes Afework Mebratu[SUP] 1 [/SUP]
Affiliations
- PMID: 40627391
- DOI: 10.1073/pnas.2424367122
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 BIK gene, 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 β5, a subunit of the proteasome, leading to increased BIK levels and enhanced viral replication. Conversely, β5 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-β5 axis that governs viral replication, suggesting that targeting BIK or β5 may offer therapeutic strategies against influenza.
Keywords: BIK; Beta 5; Influenza A virus; Proteasome; SNP.