Virus yields clues into immune system

Diagram of protein being ejected from a cell

Tricking the immune system: A malformed protein is ejected from the endoplasmic reticulum (ER) and shredded up by the proteasome. Scraps of the protein are sent back into the ER where the MHC complex shuttles them to the cell surface and the immune system examines them for any viral traces.

May 31, 2006

Tags: Ploegh LabImmune System

CAMBRIDGE, Mass. (May 31, 2006) — Since many viruses have spent hundreds of thousands of years fine-tuning their abilities to hijack the cellular processes of other organisms, we can learn a great deal about how our own cells operate by studying these pathogens at work.

Investigating one form of the herpes virus, researchers in the lab of Whitehead Member Hidde Ploegh now have discovered a key component in the machinery with which cells dispose of misfolded proteins.

“Viruses and other pathogens are simply mirror images of our immune system,” says Ploegh, senior author on the article that will be published online May 31 in Nature. “The two have really co-evolved. By studying one, we learn about the other.”

Cells have a very elegant process for disposing of proteins that have mutated or misfolded, a process that involves a cellular organ called the endoplasmic reticulum, or the ER.

The ER is a factory of sorts, the site where proteins learn how to assume their requisite shapes. But as in all intricate biological processes, a lot can go wrong when a protein folds. Moreover, cellular life exposes proteins to lots of “wear and tear.”

In order to prevent misfolded proteins from accumulating and causing conditions such as Alzheimer’s and Parkinson’s, the ER can dispose of these molecules through a process called dislocation, 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 where a mechanism called the MHC (major histocompability complex) 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 shredded protein parts for anything that bears the mark of a foreign invader. If just one of the remnants evidences viral features, the immune system swiftly destroys the cell.

This mechanism is bad news for viruses. These foreign invaders parasitically feed off of cells. If one of their own protein products 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.

“This virus has spent a long time looking for this pathway’s Achilles heel,” says Ploegh, who is also a professor of biology at MIT. “For that reason, it’s an invaluable resource for probing this dislocation pathway.” In other words, to learn more about how the cell disposes of misfolded proteins under normal conditions, one should closely study how HCMV operates.

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 former graduate student Brendan Lilley 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 (signal peptide peptidase) cooperates with US2 and is essential for the virus’s ability to disarm the cell.

“We now believe that we’ve stumbled over a previously unknown function for SPP in helping the cell get rid of malformed proteins,” says Lourerio.

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.

“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,” continues Loureiro. “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 teach us more about how the ER functions in normal circumstances.

This research was supported by grants from the National Institutes of Health.

Written by David Cameron.

* * *
Hidde Ploegh’s primary affiliation is with Whitehead Institute of Biomedical Research, where his laboratory is located and all his research conducted. He also is a professor of biology at Massachusetts Institute of Technology.
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Nature, May 31 2006, early online publication

ÒSignal peptide peptidase is required for dislocation from the endoplasmic reticulumÓ

Authors: Joana Loureiro(1 ), Brendan N. Lilley(1 ), Eric Spooner(2 ), Vanessa Noriega(3), Domenico Tortorella(3), Hidde L. Ploegh(1 )

(1) Department of Pathology, Harvard Medical School, Boston, MA
(2) Pathology Functional Proteomics Center, Harvard Medical School, Boston, MA
(3) Department of Microbiology, Mount Sinai School of Medicine, New York, NY

 Present addresses: Whitehead Institute for Biomedical Research, Cambridge, MA

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