While our immune system is usually able to identify and destroy pathogenic invaders like bacteria and viruses, those microbes have found ways to evade some of our immune defenses. Researchers have now identified a mechanism used to evade the immune system in a virus that can cause cancer, called Kaposi's sarcoma-associated herpesvirus (KSHV). The findings have been reported in the Proceedings of the National Academy of Sciences (PNAS), and they show how this and potentially other cancer-causing viruses get around the immune responses that are aimed at stopping tumor growth.
"The human immune system is normally very effective in the recognition of viral infection and the subsequent launching of antiviral defenses," noted Qian Yin, an Assistant Professor of Biological Science at Florida State University. We have sensors in the immune system that can detect the RNA and DNA that comes from viruses, and when those molecules are detected, it triggers potent antiviral responses.
"Therefore, in order for viruses to establish infection and persist in the host, viruses have evolved elaborate mechanisms to evade these host immune responses. Our work is particularly interested in how this evasion is achieved," Yin explained.
An enzymatic molecule called cyclic GMP-AMP synthase, (cGAS) acts as a critical sensor of viral DNA. It can also bind to double-stranded DNA to trigger pro-inflammatory, antiviral pathways that reduce the action of a pathogen, or stop it completely. Many viruses have targeted cGAS because of this crucial antiviral role.
In 2015, KSHV was shown to generate a protein called KicGAS that acts as an inhibitor of cGAS. In this study, the researchers deciphered the crystal structure of KicGAS. It contains simple units that repeat and form a long chain, which enables it to efficiently bind to DNA, and inhibit the binding of cGAS, explained study co-author and Professor of Biological Science Fanxiu Zhu.
"The unexpected polymeric nature of this viral protein separates it from other known viral relatives, which also hints at co-evolution between the viruses and their hosts," noted Zhu.
KSHV is also one of seven viruses that are known to cause cancer; together, these viruses are thought to be to blame for about 15 percent of cancers; KSHV can lead to primary effusion lymphoma, a subset of multicentric Castleman disease, and Kaposi's sarcoma.
cGAS also has an antitumor role. Learning how KSHV stops cGAS from working is essential for us to understand how viruses can cause cancer, noted study co-author and postdoctoral scholar Debipreeta Bhowmik.
Sources: Florida State University, Proceedings of the National Academy of Sciences
