Targeting USP22 to promote K63-linked ubiquitination and degradation of SARS-CoV-2 nucleocapsid protein

• DOI: 10.1128/jvi.02234-24
• Publication Date: 2025-04-04T16:28:08Z
• Authors: Xin Xiao; Shifeng Li; Zhijin Zheng; Yingying Ji; Qian Du; Yibo Zuo; Ying Miao; Yukang Yuan; Hui Zheng; Fang Huang; Jun Wang
• Keywords: Deubiquitinating enzyme; Coronavirus; Nidovirales; Protein Degradation

ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) generally hijacks the cellular machinery of host cells for survival. However, how SARS-CoV-2 employs host’s deubiquitinase to facilitate virus replication remains largely unknown. In this study, we identified USP22 as a crucial regulator expression nucleocapsid protein (SARS-CoV-2 NP), which is essential replication. We demonstrated that NP proteins undergo ubiquitination-dependent degradation in cells, while interacts with and downregulates K63-linked polyubiquitination NP, thereby protecting from degradation. Importantly, further revealed sulbactam, an antibiotic, can reduce levels, eventually promoting vitro vivo . This study reveals mechanism by SARS-CoV-2-encoded survival provides potential strategy fight against infection. IMPORTANCE NP) plays pivotal role viral infection binding RNA, stabilizing genome, interactions between intracellular had not been elucidated. provide evidence ubiquitination. reduction ubiquitination effectively prevents enhancing its stability, marking target antiviral strategies. Additionally, our findings indicate sulbactam significantly decreases levels USP22, reducing levels. discovery suggests novel therapeutic pathway could be repurposed agent, demonstrating certain antibiotics might contribute treatment. work thus opens avenues drug repurposing highlights targeting pathways inhibit