IKKα dependent activation of the β-catenin pathway is required for endosomal maturation and SARS-CoV-2 entry

ABSTRACT: COVID-19 is a complex disease characterized by fulminant replication of SARS-CoV-2 and associated virus-induced comorbidities. While the virus impedes induction and activity of host-protective antiviral processes, it at the same time induces exacerbated expression and function of NF-κB dependent inflammatory cytokines, leading to a hyperinflammatory syndrome associated with viral pathology. Here we identified a yet uncharacterized link between components of the NF-κB pathway and the maturation of endolysosomes, which is essential for SARS-CoV-2 entry. Chemical inhibition or genetic ablation of IKKα and NIK kinases prevents virus infection while other downstream components of the NF-κB signaling cascade are dispensable. Notably, IKKα is required for acidification of intracellular vesicles, which is an essential step in the SARS-CoV-2 infection process and inhibition of this kinase traps SARS-CoV-2 in endolysosomal compartments. Phosphoproteomic and transcriptomic analysis identified an unexpected link between IKKα and activation of the β-catenin pathway, which is known for its involvement in promoting the endosomal pathway. We propose that the aggravated NF-κB response, which is prominently observed in COVID-19 patients, facilitates SARS-CoV-2 infection through increased IKKα activity. Notably, although we identified this pathway to be essential for SARS-CoV-2 entry, we demonstrate that the activity IKKα is generally required for full maturation of endolysosomes.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Severe Acute Respiratory Syndrome Coronavirus 2

TISSUE(S): Lung, Epithelial Cell

SUBMITTER: Quirin Emslander  

LAB HEAD: Andreas Pichlmair

PROVIDER: PXD036627 | Pride | 2026-08-03

REPOSITORIES: Pride