Abstract
Cytotoxic T lymphocytes (CTLs) are the major killer of virus-infected cells. Granzyme B (GrB) from CTLs induces apoptosis in target cells by cleavage and activation of substrates like caspase-3 and Bid. However, while undergoing apoptosis, cells are still capable of producing infectious viruses unless a mechanism exists to specifically inhibit viral production. Using proteomic approaches, we identified a novel GrB target that plays a major role in protein synthesis: eukaryotic initiation factor 4 gamma 3 (eIF4G3). We hypothesized a novel role for GrB in translation of viral proteins by targeting eIF4G3, and showed that GrB cleaves eIF4G3 specifically at the IESD1408S sequence. Both GrB and human CTL treatment resulted in degradation of eIF4G3 and reduced rates of translation. When Jurkat cells infected with vaccinia virus were treated with GrB, there was a halt in viral protein synthesis and a decrease in production of infectious new virions. The GrB-induced inhibition of viral translation was independent of the activation of caspases, as inhibition of protein synthesis still occurred with addition of the pan-caspase inhibitor zVAD-fmk. This demonstrated for the first time that GrB prevents the production of infectious vaccinia virus by targeting the host translational machinery.
Highlights
One major strategy of the host to survive the attack of viruses is to induce apoptosis in infected host cells
We identified a new role of granzyme B in preventing viral replication during the killing process
We found that granzyme B disables the ability of the host cell to make new proteins, including viral proteins of infected cells
Summary
One major strategy of the host to survive the attack of viruses is to induce apoptosis in infected host cells. Cytotoxic T-lymphocytes (CTLs) play an important role in the apoptosis pathway, which activates a family of cytosolic proteins called caspases in target cells. They execute the key reactions that drive target cells to their demise. Activation of initiator caspases such as caspase-8 and 10 results in direct activation of the apoptosis executioner caspases like caspase-3 [1]. Caspase-8 and 10 signal through the mitochondrial pathway by activating a protein called ‘‘BH3 interacting domain death agonist’’ (Bid) [2,3], resulting in the release of cytochrome c (cyt c). Soluble cyt c mediates the activation of the executioner caspases [1]. Other substrates of executioner caspases include cytoskeletal and nuclear skeletal components like fodrin and lamin A, which result in cell shrinkage [1]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
