Cereblon promotes influenza virus replication through AMPK ubiquitination

Abstract Influenza A and B viruses (IAV and IBV) continually threaten global health, with IAV posing a risk of emerging pandemics. Rapid viral evolution makes current treatments less effective, highlighting the urgent need for broad-spectrum antivirals. Targeting host factors essential for viral replication may offer a highly promising broad-spectrum antiviral strategy. In this context, cereblon (CRBN), a substrate adaptor of the CRL4 E3 ubiquitin ligase complex, is found to promote both IAV and IBV replication as a key pro-viral host factor. Mechanistically, CRBN targets and degrades AMP-activated protein kinase (AMPK) via the proteasome. This CRBN-driven degradation shifts the metabolism of the infected cells toward anabolism, promoting lipid droplet (LD) formation and creating a microenvironment favorable for viral replication. Genetic depletion or inhibition of CRBN stabilizes AMPK, significantly reduces LD formation, and effectively suppresses the replication of various IAV and IBV strains in vivo, demonstrating its broad-spectrum potential. Notably, Crbn knockout mice show marked resistance to lethal IAV infection. CRBN inhibition with immunomodulatory imide drugs—known CRBN inhibitors—significantly decreases IAV replication in vivo. This research underscores CRBN as a crucial regulator of host metabolism during viral infection, revealing the CRBN-AMPK axis as a promising target for host-directed pan-influenza antiviral development. Author Summary Influenza A and B viruses are response for recurring seasonal epidemics and occasional pandemics that pose serious global health challenges. Current antiviral drugs often lose effectiveness as influenza viruses rapidly develop resistance through genetic mutations. To overcome this limitation, our study focused on a host factor targeted by influenza viruses-the ubiquitin E3 ligase substrate adaptor cereblon (CRBN). We discovered that influenza viruses exploit CRBN to enhance their replication by altering host cell metabolism. Specifically, CRBN binds to a key energy sensor – AMPKα and induces the ubiquitination and degradation of AMPKγ. Consequently, the AMPK suppression shifts the cellular environment from catabolism to anabolism, activating lipogenic enzymes and promoting lipid droplets formation which provide a favorable environment for viral growth. Our study highlight that blocking CRBN either genetically or chemical inhibition (immunomodulatory imide drugs) of CRBN reduces LD formation and strongly suppresses diverse influenza strains replication in vitro and in vivo. These findings reveal not only how viruses hijack host metabolism via the CRBN-AMPK pathway but also present a potential therapeutic for novel broad-spectrum anti-influenza. Competing Interest Statement K.-O.C. is a board member at Pharmacolinx, and I.G.G is a board member at Recursion. All other authors declare that they have no competing interests.