Since many viruses have spent hundreds of thousands of years fine-tuning their abilities to hijack the cellular processes of other organisms, scientists have been able to learn a great deal about how human cells operate by studying these pathogens.
Investigating one form of the herpes virus, researchers in the lab of Whitehead member and MIT Professor of Biology Hidde Ploegh have now discovered a key component in the machinery that cells use to dispose of misfolded proteins. The accumulation of such proteins can lead to conditions such as Alzheimer's and Parkinson's.
"Viruses and other pathogens are simply mirror images of our immune system," said Ploegh, senior author on an article published online May 31 in Nature. "The two have really co-evolved. By studying one, we learn about the other."
Cells have an elegant process for disposing of proteins that have mutated or misfolded. A cellular organ called the endoplasmic reticulum, or ER, can dispose of these molecules through dislocation, a process first discovered by Ploegh and colleagues in 1996 during his tenure at MIT's Center for Cancer Research.
In dislocation, the ER marks broken proteins with a chemical tag that flags them for disposal. Once ejected from the ER, a complex called the proteasome captures the flagged protein and shreds it to pieces. The protein's remains are then sent back to the ER and the major histocompatibility complex (MHC) shuttles the fragments up to the cell surface and showcases them to the immune system.
There, like a policeman examining a suspect's trash for evidence, the immune system pores over these protein parts for anything that bears the mark of a foreign invader. If just one remnant evidences viral features, the immune system swiftly destroys the cell.
This mechanism is bad news for viruses, foreign invaders that parasitically feed off cells. If one viral protein product gets shredded by the proteasome and shuttled to the cell surface by the MHC, the game's over.
One virus that has figured out a way to work around this is human cytomegalovirus, or HCMV, a generally harmless form of herpes. This virus can trick the cell into mistaking the MHC for a misfolded protein, which the cell then puts out with the trash. Without the MHC, the cell has no effective way of alerting the immune system to a viral presence, and the virus can proliferate unencumbered.
The Ploegh lab singled out two proteins, US2 and US11, essential for the herpes virus to bypass immune detection by shuttling MHC into a degradation pathway. While a former graduate student had discovered molecules that interact with US11, US2 remained more of a mystery. Graduate student Joana Loureiro and colleagues found that a protein called SPP cooperates with US2 and is essential for the virus's ability to disarm the cell.
Normally, SPP's job is to break up small proteins called signal peptides, which are important for other aspects of immune surveillance -- a function not related to dislocation.
"We now believe that we've stumbled over a previously unknown function for SPP in helping the cell get rid of malformed proteins," Loureiro said.
"There are many common diseases that are caused by expression of a defective form of a protein, like cystic fibrosis, or accumulation of misfolded proteins, as is thought to be the case for Alzheimer's," Loureiro said. "Any molecule that we can find that contributes to the general process of ER protein disposal is an important discovery."
The next step is to figure out precisely how these two proteins, US2 and SPP, collaborate. That work likely will reveal additional molecules that the virus uses, which will ultimately reveal more about how the ER functions in normal circumstances.
This research was supported by the National Institutes of Health.
