Virus yields clues into immune 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.”
“There are many common diseases that
are caused by expression of a defective form of
a protein,” says graduate student Joana
Loureiro. “Any molecule that we can find
that contributes to the general process of ER
protein disposal is an important discovery.” |
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.
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