2. Academic Validation
  3. KSHV vIL-6 promotes SIRT3-induced deacetylation of SERBP1 to inhibit ferroptosis and enhance cellular transformation by inducing lipoyltransferase 2 mRNA degradation

KSHV vIL-6 promotes SIRT3-induced deacetylation of SERBP1 to inhibit ferroptosis and enhance cellular transformation by inducing lipoyltransferase 2 mRNA degradation

  • PLoS Pathog. 2024 Mar 12;20(3):e1012082. doi: 10.1371/journal.ppat.1012082.
Jing Zhou 1,  Tianjiao Wang 1,  Haoran Zhang 1,  Jianhong Liu 2,  Pengjun Wei 1,  Ruoqi Xu 1,  Qin Yan 1 3 4,  Guochun Chen 5,  Wan Li 1 3 4,  Shou-Jiang Gao 6,  Chun Lu 1 3 4
Affiliations

Affiliations

  • 1 Department of Microbiology, Nanjing Medical University, Nanjing, People's Republic of China.
  • 2 Department of Pathology, Changzhou Third People's Hospital, Changzhou, People's Republic of China.
  • 3 Changzhou Medical Center, Nanjing Medical University, Nanjing, People's Republic of China.
  • 4 Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, People's Republic of China.
  • 5 Department of Infectious Diseases, Changzhou Third People's Hospital, Changzhou, People's Republic of China.
  • 6 Tumor Virology Program, UPMC Hillman Cancer Center, and Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
PMID: 38470932 DOI: 10.1371/journal.ppat.1012082
Abstract

Ferroptosis, a defensive strategy commonly employed by the host cells to restrict pathogenic infections, has been implicated in the development and therapeutic responses of various types of Cancer. However, the role of Ferroptosis in oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV)-induced cancers remains elusive. While a growing number of non-histone proteins have been identified as acetylation targets, the functions of these modifications have yet to be revealed. Here, we show KSHV reprogramming of host acetylation proteomics following cellular transformation of rat primary mesenchymal precursor. Among them, SERPINE1 mRNA binding protein 1 (SERBP1) deacetylation is increased and required for KSHV-induced cellular transformation. Mechanistically, KSHV-encoded viral interleukin-6 (vIL-6) promotes SIRT3 deacetylation of SERBP1, preventing its binding to and protection of lipoyltransferase 2 (Lipt2) mRNA from mRNA degradation resulting in Ferroptosis. Consequently, a SIRT3-specific inhibitor, 3-TYP, suppresses KSHV-induced cellular transformation by inducing Ferroptosis. Our findings unveil novel roles of vIL-6 and SERBP1 deacetylation in regulating Ferroptosis and KSHV-induced cellular transformation, and establish the vIL-6-SIRT3-SERBP1-ferroptosis pathways as a potential new therapeutic target for KSHV-associated cancers.

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