{ "abstract": "TRAF6 is traditionally recognized as an antiviral ubiquitin E3 ligase that positively regulates the production of type I interferon and inflammatory cytokines. However, our study reveals that TRAF6 also plays a crucial role in the lytic replication of Kaposi’s sarcoma-associated herpesvirus (KSHV). Mechanistically, during KSHV lytic replication, TRAF6 mediates the K63-linked polyubiquitination and activation of Akt, which is required for the efficient viral replication. Disruption of TRAF6 or Akt expression through CRISPR-mediated knockout, or inhibition of TRAF6 or Akt with small molecule inhibitors, reduces KSHV replication efficiency. Conversely, expression of constitutively active Akt can rescue the impaired replication caused by TRAF6 deficiency. Notably, the TRAF6-Akt axis is also required for the lytic replication of Epstein-Barr virus but not for Human cytomegalovirus. These findings highlight the role of the TRAF6-Akt axis in the life cycle of oncogenic herpesviruses and suggest potential therapeutic targets for related diseases. Author summary: Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) are cancer-causing viruses that establish lifelong infections in humans. To survive and multiply, these viruses must cleverly manipulate the host cell they infect. A host protein called TRAF6 is traditionally known as an immune system “defender” that helps the body fight off viral infections by triggering inflammation. However, our study reveals a surprising twist: these cancer-causing herpesviruses actually hijack TRAF6 to promote their own replication. We found that during the lytic phase of KSHV infection, TRAF6 acts as a switch to turn on another host protein called Akt. This TRAF6-Akt axis provides an essential signal that allows the virus to multiply efficiently.", "abstract_shown": true, "affiliations": [ "Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Children’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China", "Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China", "Department of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China", "State Key Laboratory of Developmental Biology of Freshwater Fish, Human International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China", "Shanghai Key Laboratory of Severe Respiratory Infection, Shanghai, China" ], "article_type": "Research Article", "arxiv": null, "author_total": 7, "authors": [ { "affs": [ 0 ], "name": "Zhenshan Liu" }, { "affs": [ 1 ], "name": "Qingyu Guo" }, { "affs": [ 2 ], "name": "Weili Wang" }, { "affs": [ 3 ], "name": "Hongjia Lu" }, { "affs": [ 4 ], "name": "Tianyu Yu" }, { "name": "Tingting Li" }, { "name": "Qiming Liang" } ], "bibtex": "https://research.draconitic.com/paper/9jjn1dgxygnkd.bib", "cited_by": 0, "doi": "10.1371/journal.ppat.1014557", "fulltext_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014557", "id": "9jjn1dgxygnkd", "issns": [ "1553-7374" ], "landing_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014557", "language": null, "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2730|Viral-associated cancers and disorders" ], [ "plos", "/Biology and life sciences/Biochemistry/Enzymology/Enzymes/Ligases" ], [ "plos", "/Biology and life sciences/Biochemistry/Nucleic acids/DNA/DNA replication" ], [ "plos", "/Biology and life sciences/Biochemistry/Proteins/Enzymes/Ligases" ], [ "plos", "/Biology and life sciences/Biochemistry/Proteins/Immune system proteins/Antibodies" ], [ "plos", "/Biology and life sciences/Biochemistry/Proteins/Post-translational modification/Ubiquitination" ], [ "plos", "/Biology and life sciences/Genetics/DNA/DNA replication" ], [ "plos", "/Biology and life sciences/Immunology/Immune system proteins/Antibodies" ], [ "plos", "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Viral pathogens/Herpesviruses/Epstein-Barr virus" ], [ "plos", "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Viral pathogens/Herpesviruses/Kaposi's sarcoma-associated herpesvirus" ], [ "plos", "/Biology and life sciences/Microbiology/Virology/Viral replication" ], [ "plos", "/Biology and life sciences/Molecular biology/Molecular biology techniques/Biomolecular isolation/DNA isolation" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/DNA viruses/Herpesviruses/Epstein-Barr virus" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/DNA viruses/Herpesviruses/Kaposi's sarcoma-associated herpesvirus" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/Viral pathogens/Herpesviruses/Epstein-Barr virus" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/Viral pathogens/Herpesviruses/Kaposi's sarcoma-associated herpesvirus" ], [ "plos", "/Biology and life sciences/Physiology/Immune physiology/Antibodies" ], [ "plos", "/Medicine and health sciences/Immunology/Immune system proteins/Antibodies" ], [ "plos", "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Viral pathogens/Herpesviruses/Epstein-Barr virus" ], [ "plos", "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Viral pathogens/Herpesviruses/Kaposi's sarcoma-associated herpesvirus" ], [ "plos", "/Research and analysis methods/Molecular biology techniques/Biomolecular isolation/DNA isolation" ] ], "openalex": "W7206200630", "pdf_url": "https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1014557&type=printable", "pmcid": null, "pmid": null, "published": "2026-09-01", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/9jjn1dgxygnkd.ris", "sources": [ { "first_seen": "2026-10-30T12:18:02Z", "native_id": "10.1371/journal.ppat.1014557", "source": "plos", "url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014557" } ], "subjects": [ { "field": "biology", "origin": "plos:immunology", "subfield": "immunology" }, { "field": "biology", "origin": "plos:microbiology", "subfield": "microbiology" } ], "title": "The TRAF6-Akt axis is required for efficient lytic replication of KSHV", "title_text": "The TRAF6-Akt axis is required for efficient lytic replication of KSHV", "type": "peer-reviewed", "updated_at": "2026-10-30T12:18:02Z", "url": "https://research.draconitic.com/paper/9jjn1dgxygnkd", "venue": "PLOS Pathogens", "versions": [] }