2. Academic Validation
  3. Non-canonical regulation of the reactivation of an oncogenic herpesvirus by the OTUD4-USP7 deubiquitinases

Non-canonical regulation of the reactivation of an oncogenic herpesvirus by the OTUD4-USP7 deubiquitinases

  • PLoS Pathog. 2024 Jan 12;20(1):e1011943. doi: 10.1371/journal.ppat.1011943.
Shaowei Wang 1 2 3,  Xuezhang Tian 1 2,  Yaru Zhou 1 2,  Jun Xie 1 2,  Ming Gao 1 2,  Yunhong Zhong 1 2,  Chuchu Zhang 1 2,  Keying Yu 2 4,  Lei Bai 5,  Qingsong Qin 6,  Bo Zhong 2 4,  Dandan Lin 7,  Pinghui Feng 8,  Ke Lan 2 5,  Junjie Zhang 1 2 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, State Key Laboratory of Virology, Medical Research Institute, Wuhan University, Wuhan, China.
  • 2 Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China.
  • 3 Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Province Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
  • 4 Department of Gastrointestinal Surgery, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
  • 5 State Key Laboratory of Virology, School of Life Sciences, Wuhan University, Wuhan, China.
  • 6 Laboratory of Human Virology and Oncology, Shantou University Medical College, Shantou, China.
  • 7 Cancer Center, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China.
  • 8 Section of Infection and Immunity, Herman Ostrow School of Dentistry, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America.
PMID: 38215174 DOI: 10.1371/journal.ppat.1011943
Abstract

Deubiquitinases (DUBs) remove ubiquitin from substrates and play crucial roles in diverse biological processes. However, our understanding of deubiquitination in viral replication remains limited. Employing an oncogenic human herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) to probe the role of protein deubiquitination, we found that Ovarian tumor family Deubiquitinase 4 (OTUD4) promotes KSHV reactivation. OTUD4 interacts with the replication and transcription activator (K-RTA), a key transcription factor that controls KSHV reactivation, and enhances K-RTA stability by promoting its deubiquitination. Notably, the DUB activity of OTUD4 is not required for K-RTA stabilization; instead, OTUD4 functions as an adaptor protein to recruit another DUB, USP7, to deubiquitinate K-RTA and facilitate KSHV lytic reactivation. Our study has revealed a novel mechanism whereby KSHV hijacks OTUD4-USP7 deubiquitinases to promote lytic reactivation, which could be potentially harnessed for the development of new Antiviral therapies.

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