An international research team has discovered a protein that allows a group of herpes viruses to shut down an antiviral defence. The findings, published in the Journal of Cell Biology, show how viruses succeed in eluding the human body's immune system.
The Dutch, UK and US researchers have found that cytomegalovirus (a common virus that is part of the herpes group of viruses which can cause birth defects or cold sores) singles out the protein called major histocompatibility complex class I (MHC I) and renders it ineffective.
MHC I helps people who are under the weather by capturing viral proteins fragments and presenting them to cytotoxic T cells (killer T cells). These cytotoxic T cells kill cells that are infected with viruses or other pathogens, or are otherwise damaged or dysfunctional.
According to the researchers, two cytomegalovirus genes – US2 and US11 – fool cells into ubiquitinating (making proteins inactive by attaching ubiquitin to them) the MHC I protein. Ubiquitin is a key protein that gives the 'kiss of death' to other proteins.
'The US2 and US11 gene products of human cytomegalovirus promote viral evasion by hijacking the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway,' the research showed.
Once this happens, the cytomegalovirus genes demolish MHC I in the proteasome (large protein complexes), whose main function it is to reduce unneeded or damaged proteins. 'US2 and US11 initiate dislocation of newly translocated MHC I from the ER to the cytosol for proteasome-mediated degradation, thereby decreasing cell surface MHC I.'
MHC I ubiquitination begins when the cytomegalovirus genes co-opt the cellular protein called E3 ligase.
Lead author Helen R. Stagg of the Cambridge Institute for Medical Research at the University of Cambridge in the UK, along with her colleagues, screened 373 ligases by depleting them one by one with RNAi (ribonucleic acid (RNA) interference). RNAi is a system within living cells that helps control which genes are active and how active they are. According to the research team, they knocked down a ligase called TRC8 which helped safeguard MHC I.
'Of the 373 ligases screened, only siRNA-mediated depletion of TRC8 gave a significant rescue in fluorescence signal above the Bonferroni-corrected p-value threshold of 3.82,' the authors wrote.
MHC I can do its job when the mutant version of TRC8 restricts ubiquitination. While little is known about how the protein works, researchers recognise that MHC I is mutated in some rare hereditary and sporadic kidney tumours. Experts speculate that one of the normal targets of TRC8 encourages cancer.
'The involvement of TRC8 in both hereditary and sporadic cases of clear cell renal carcinoma is intriguing, particularly as TRC8 is the second E3 ligase, after the von Hippel-Lindau gene product, to be implicated in the aetiology of renal tumours,' the authors wrote. 'Because disruption of TRC8 predisposes to renal cell carcinoma, increasing levels of proteins usually disposed of by TRC8 may be involved in tumour development, making the identification of physiological substrates of this novel ERAD E3 ligase all the more imperative.'
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