Biology subjects

Choi, H.-S.

Publications and source records attributed to Choi, H.-S..

3 recordsLinked to original sources

bioRxiv2025

Cereblon Promotes Influenza Virus Replication through AMPK Ubiquitination

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 SummaryInfluenza 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 - AMPK and induces the ubiquitination and degradation of AMPK{gamma}. 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.

microbiology↗

bioRxiv2022

Targeted Kinase Degradation via the KLHDC2 Ubiquitin E3 Ligase

Chemically induced protein degradation is a powerful strategy for perturbing cellular biochemistry. The predominant mechanism of action for protein degrader drugs involves induced proximity between the cellular ubiquitin conjugation machinery and the target. Unlike traditional small molecule enzyme inhibition, targeted protein degradation can clear an undesired protein from cells. We demonstrate here the use of peptide ligands for Kelch-Like Homology Domain Containing protein 2 (KLHDC2), a substrate adaptor protein and member of the cullin-2 (CUL2) ubiquitin ligase complex, for targeted protein degradation. Peptide-based bivalent compounds that can induce proximity between KLHDC2 and target proteins cause degradation of the targeted factors. The cellular activity of these compounds depends on KLHDC2 binding. This work demonstrates the utility of KLHDC2 for targeted protein degradation and exemplifies a strategy for the rational design of new peptide-based ligands useful for this purpose.

biochemistry↗

bioRxiv2017

The Molecular Link Between Auxin And ROS-Mediated Polar Growth

Root hair polar growth is endogenously controlled by auxin and sustained by oscillating levels of reactive oxygen species (ROS). These cells extend several hundred-fold their original size toward signals important for plant survival. Although their final cell size is of fundamental importance, the molecular mechanisms that control it remain largely unknown. Here, we show that ROS production is controlled by the transcription factors RSL4, which in turn is transcriptionally regulated by auxin through several Auxin Responsive Factors (ARFs). In this manner, auxin controls ROS-mediated polar growth by activating RSL4, which then upregulates the expression of genes encoding NADPH oxidases (also known as RBOHs, RESPIRATORY BURST OXIDASE HOMOLOG proteins) and Class-III Peroxidases (PER), which catalyse ROS production. Chemical or genetic interference with the ROS balance or peroxidase activity affect root hair final cell size. Overall, our findings establish a molecular link between auxin regulated ARFs-RSL4 and ROS-mediated polar root hair growth.\n\nSignificance StatementTip-growing root hairs are excellent model systems to decipher the molecular mechanism underlying reactive oxygen species (ROS)-mediated cell elongation. Root hairs are able to expand in response to external signals, increasing several hundred-fold their original size, which is important for survival of the plant. Although their final cell size is of fundamental importance, the molecular mechanisms that control it remain largely unknown. In this study, we propose a molecular mechanism that links the auxin-Auxin Response Factors (ARFs) module to activation of RSL4, which directly targets genes encoding ROS-producing enzymes, such as NADPH oxidases (or RBOHs) and secreted type-III peroxidases (PERs). Activation of these genes impacts apoplastic ROS homeostasis, thereby stimulating root hair cell elongation.

plant biology↗