Cyclophilin A binds to AKT1 and facilitates the tumorigenicity of Epstein-Barr virus by mediating the activation of AKT/mTOR/NF-κB positive feedback loop

  • Virol Sin. 2022 Sep 6;S1995-820X(22)00149-3. doi: 10.1016/j.virs.2022.09.001.
Shuyu Xin  1 ,  Lingzhi Liu  1 ,  Yanling Li  2 ,  Jing Yang  3 ,  Lielian Zuo  3 ,  Pengfei Cao  4 ,  Qijia Yan  5 ,  Shen Li  2 ,  Li Yang  2 ,  Taimei Cui  6 ,  Jianhong Lu  7
Affiliations
  • 1. Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China; Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, 410078, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, NHC Key Laboratory of Carcinogenesis, Cancer Research Institute, Central South University, Changsha, 410078, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410013, China; Department of Hematology, National Clinical Research Center for Geriatric Disorders, Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410080, China.
  • 2. Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China; Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, 410078, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, NHC Key Laboratory of Carcinogenesis, Cancer Research Institute, Central South University, Changsha, 410078, China.
  • 3. Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, NHC Key Laboratory of Carcinogenesis, Cancer Research Institute, Central South University, Changsha, 410078, China.
  • 4. The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, NHC Key Laboratory of Carcinogenesis, Cancer Research Institute, Central South University, Changsha, 410078, China; Department of Hematology, National Clinical Research Center for Geriatric Disorders, Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410080, China.
  • 5. Department of Hematology, National Clinical Research Center for Geriatric Disorders, Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410080, China.
  • 6. Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, 410078, China.
  • 7. Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China; Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, 410078, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, NHC Key Laboratory of Carcinogenesis, Cancer Research Institute, Central South University, Changsha, 410078, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410013, China; Department of Hematology, National Clinical Research Center for Geriatric Disorders, Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410080, China. Electronic address: [email protected].
PMID: 36075565 DOI: 10.1016/j.virs.2022.09.001
Abstract

The Akt/mTOR and NF-κB signalings are crucial pathways activated in cancers including nasopharyngeal carcinoma (NPC), which is prevalent in southern China and closely related to Epstein-Barr virus (EBV) Infection. How these master pathways are persistently activated in EBV-associated NPC remains to be investigated. Here we demonstrated that EBV-encoded latent membrane protein 1 (LMP1) promoted Cyclophilin A (CYPA) expression through the activation of NF-κB. The depletion of CYPA suppressed cell proliferation and facilitated Apoptosis. CYPA was able to bind to Akt1, thus activating Akt/mTOR/NF-κB signaling cascade. Moreover, the use of mTOR Inhibitor, rapamycin, subverted the activation of the positive feedback loop, NF-κB/CYPA/Akt/mTOR. It is reasonable that LMP1 expression derived from initial viral Infection is enough to assure the constant potentiation of Akt/mTOR and NF-κB signalings. This may partly explain the fact that EBV serves as a tumor-promoting factor with minimal expression of the viral oncoprotein LMP1 in malignancies. Our findings provide new insight into the understanding of causative role of EBV in tumorigenicity during latent Infection.

Keywords
Cyclophilin A (CYPA); Epstein-barr virus (EBV); Latent membrane protein 1 (LMP1); NF-κB/AKT/mTOR signaling; Tumorigenicity.
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