Non-structural Protein of Crimean-Congo Hemorrhagic Fever Virus Disrupts Mitochondrial Membrane Potential and Induces Apoptosis [Microbiology]

November 16th, 2015 by Barnwal, B., Karlberg, H., Mirazimi, A., Tan, Y.-J.

Viruses have developed distinct strategies to overcome the host defense system. Regulation of apoptosis in response to viral infection is important for virus survival and dissemination. Like other viruses, Crimean-Congo hemorrhagic fever virus (CCHFV) is known to regulate apoptosis. This study for the first time suggests that the non-structural protein NSs of CCHFV, a member of the genus Nairovirus, induces apoptosis. In this report, we demonstrated the expression of CCHFV NSs, which contains 150 amino acid (aa) residues, in the CCHFV-infected cells. CCHFV NSs undergoes active degradation during infection. We further demonstrated that ectopic expression of CCHFV NSs induces apoptosis, as reflected by the caspase-3/7 activity and cleaved poly(ADP-ribose) polymerase (PARP), in different cell lines that support CCHFV replication. Using specific inhibitors, we showed that CCHFV NSs induces apoptosis via both intrinsic and extrinsic pathways. The minimal active region of the CCHFV NSs protein was determined to be 93-140 aa residues. Using alanine scanning, we demonstrated that L127 and L135 are the key residues for NSs-induced apoptosis. Interestingly, CCHFV NSs co-localizes in mitochondria and also disrupts the mitochondrial membrane potential. We also demonstrated that L127 and L135 are important residues for the disruption of mitochondrial membrane potential by NSs. Thus, these results indicate that the C-terminal of CCHFV NSs triggers mitochondrial membrane permeabilization leading to activation of caspases which ultimately leads to apoptosis. Given that multiple factors contribute to apoptosis during CCHFV infection, further studies are needed to define the involvement of CCHFV NSs in regulating apoptosis in infected cells.
  • Posted in Journal of Biological Chemistry, Publications
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