E3 ubiquitin ligase ZBTB25 suppresses beta coronavirus infection through ubiquitination of the main viral protease MPro
Year: 2023
Type: article
Abstract: The main protease of severe acute respiratory syndrome coronavirus 2, Mpro, is a key viral protein essential for viral infection and replication. Mpro has been the target of many pharmacological efforts; however, the host-specific regulation of Mpro protein remains unclear. Here, we report the ubiquitin-proteasome-dependent degradation of Mpro protein in human cells, facilitated by the human E3 ubiquitin ligase ZBTB25. We demonstrate that Mpro has a short half-life that is prolonged via proteasomal inhibition, with its Lys-100 residue serving as a potential ubiquitin acceptor. Using in vitro binding assays, we observed ZBTB25 and Mpro bind to each other in vitro, and using progressive deletional mapping, we further uncovered the required domains for this interaction. Finally, we used an orthologous beta-coronavirus infection model and observed that genetic ablation of ZBTB25 resulted in a more highly infective virus, an effect lost upon reconstitution of ZBTB25 to deleted cells. In conclusion, these data suggest a new mechanism of Mpro protein regulation as well as identify ZBTB25 as an anticoronaviral E3 ubiquitin ligase.
Source: Journal of Biological Chemistry
Authors: Travis B. Lear, Áine N. Boudreau, Karina C. Lockwood, Elise Chu, Daniel P. Camarco, Qing Cao, Matthew Nguyen, John W. Evankovich, Toren Finkel, Yuan Liu, Bill B. Chen
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,800
Awards: G1174058677, G2171262792, G3101222702, Vascular autophagy as a mediator of vascular aging and homeostasis, G4365909528, G4992098652, G5480541558, The role of calcium entry through the mitochondrial uniporter in regulating cardiac metabolism and physiology, G640327682, G6454741633, G714219889, G7229429746, Modulating Alzheimer’s Disease by mTORC1 inhibition to augment lysosomal activity, G9000021181, G9000089232, G9000093630, G9000096086, G9000169778, G9000173315, G9000256038, G9000317322, G9000324584
OpenAlex ID: W4387978153