Herpesviruses shape tumour microenvironment through exosomal transfer of viral microRNAs

PLoS Pathogens

Yifat Ofir-Birin¹  Neta Regev-Rudzki¹  Stephen Henderson²  Javier Herrero²  Ohad Yogev³  Tariq Enver³  Sara Sofia Marelli³  Matthew John Hayes⁴ 

[1] Faculty of Biochemistry, Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel;UCL Cancer Institute, Bill Lyons Informatics Centre, Paul O’Gorman Building, University College London, London, England, United Kingdom;UCL Cancer Institute, Research Department of Cancer Biology, Paul O’Gorman Building, University College London, London, England, United Kingdom;UCL Institute of Ophthalmology, EM-Unit, Bath Street, London, England, United Kingdom

关键词: Exosomes;    MicroRNAs;    Cell metabolism;    Kaposi's sarcoma-associated herpesvirus;    Mitochondria;    Glycolysis;    Oxygen consumption;    Warburg effect;   

DOI  :  10.1371/journal.ppat.1006524

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Metabolic changes within the cell and its niche affect cell fate and are involved in many diseases and disorders including cancer and viral infections. Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi’s sarcoma (KS). KSHV latently infected cells express only a subset of viral genes, mainly located within the latency-associated region, among them 12 microRNAs. Notably, these miRNAs are responsible for inducing the Warburg effect in infected cells. Here we identify a novel mechanism enabling KSHV to manipulate the metabolic nature of the tumour microenvironment. We demonstrate that KSHV infected cells specifically transfer the virus-encoded microRNAs to surrounding cells via exosomes. This flow of genetic information results in a metabolic shift toward aerobic glycolysis in the surrounding non-infected cells. Importantly, this exosome-mediated metabolic reprogramming of neighbouring cells supports the growth of infected cells, thereby contributing to viral fitness. Finally, our data show that this miRNA transfer-based regulation of cell metabolism is a general mechanism used by other herpesviruses, such as EBV, as well as for the transfer of non-viral onco-miRs. This exosome-based crosstalk provides viruses with a mechanism for non-infectious transfer of genetic material without production of new viral particles, which might expose them to the immune system. We suggest that viruses and cancer cells use this mechanism to shape a specific metabolic niche that will contribute to their fitness.

【 授权许可】

CC BY