{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T06:00:14Z","timestamp":1781244014205,"version":"3.54.1"},"reference-count":97,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:00:00Z","timestamp":1781222400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82341062, 82472251"],"award-info":[{"award-number":["82341062, 82472251"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Following the global outbreak of the COVID-19 pandemic, the interactions between SARS-CoV-2 and host cells have attracted widespread attention. As crucial intracellular enzymes, E3 ubiquitin ligases are involved in numerous physiological processes, including protein degradation, cell cycle regulation, and immune responses. Recent studies have demonstrated that E3 ubiquitin ligases play a pivotal role in the interplay between SARS-CoV-2 and the host. Through interactions with host E3 enzymes, SARS-CoV-2 regulates key processes such as viral replication, immune evasion, and apoptosis. For instance, viral proteins can bind to E3 enzymes to modulate host immune responses and inhibit interferon production, thereby promoting persistent infection. Conversely, E3 enzymes can also regulate the viral life cycle and host cell survival by mediating targeted protein degradation. This mini-review summarizes the roles of E3 ubiquitin ligases in SARS-CoV-2 infection, introduces E3 ligase-mediated ubiquitin-like modifications, and discusses their underlying mechanisms at the virus-host interface. Furthermore, we highlight future research directions and potential therapeutic strategies. Understanding the functions of E3 ubiquitin ligases not only provides novel insights into the pathogenesis of SARS-CoV-2 but also offers promising targets for the development of antiviral therapeutics.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1796416","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T05:48:00Z","timestamp":1781243280000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["SARS-CoV-2-host and interactions: the dual roles of E3 ubiquitin ligases and ubiquitin-like modification mechanisms in viral infection"],"prefix":"10.3389","volume":"17","author":[{"given":"Jingyi","family":"Fu","sequence":"first","affiliation":[{"name":"Institute of Virology and AIDS Research, The First Hospital of Jilin University","place":["Changchun, Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhizhong","family":"Mi","sequence":"additional","affiliation":[{"name":"Institute of Virology and AIDS Research, The First Hospital of Jilin University","place":["Changchun, Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaolong","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Virology and AIDS Research, The First Hospital of Jilin University","place":["Changchun, Jilin, China"]},{"name":"Department of Infectious Diseases, Infectious Diseases and Pathogen Biology Center, Key Laboratory of Organ Regeneration and Transplantation of The Ministry of Education, The First Hospital of Jilin University","place":["Changchun, Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.00618-21","article-title":"MARCH8 targets cytoplasmic lysine residues of various viral envelope glycoproteins","volume":"10","author":"Zhang","year":"2022","journal-title":"Microbiol Spectr"},{"key":"B2","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1038\/s41392-023-01335-5","article-title":"The E3 ligase RNF5 restricts SARS-CoV-2 replication by targeting its envelope protein for degradation","volume":"8","author":"Li","year":"2023","journal-title":"Signal Transduct Target Ther"},{"key":"B3","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1007\/s00018-023-05011-3","article-title":"SARS-CoV-2 ORF6 protein targets TRIM25 for proteasomal degradation to diminish K63-linked RIG-I ubiquitination and type-I interferon 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