What is the Unfolded Protein Response?
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What is the Unfolded Protein Response?

October 5, 2019


Did you know that a single biological process
is related to diseases as diverse as diabetes, Parkinson’s, and cancer? The process is called the unfolded protein
response, or UPR, and it helps cells deal with problematic proteins. Proteins play many
key roles in the cell, including on the cell surface, where they help the cell communicate
with other cells in the organism. Proteins can only do their jobs if they are the correct
shape, which scientists refer to as being properly folded. Sometimes, though, they don’t
fold correctly and instead behave kind of like floppy, sticky spaghetti noodles. The UPR deals with troublesome unfolded proteins
in an internal chamber called the endoplasmic reticulum, or ER. The ER serves many functions.
Most importantly, it is where newly made proteins fold. It also serves as a quality control
center, kind of like a TSA agent at the airport. If the new proteins are in good shape, they
are allowed to go to their destinations. If they are unfolded, the ER sends them to be
degraded so they don’t gum up the works. When a cell produces lots of unfolded proteins,
the UPR kicks in. Peter Walter at UC San Francisco discovered a critical sensor protein called
Ire1 that detects when the unfolded protein level is too high and tells the cell that
it needs to make more ER. Even with this extra boost, the ER can get overwhelmed and accidentally
allow unfolded proteins to get through the quality check, which would cause devastating
problems. In these cases, the UPR tells the cell that time has run out and makes it self-destruct
so it doesn’t hurt the whole organism. So, how does the UPR relate to diabetes, Parkinson’s,
and cancer? The cells that metabolize sugar need to produce
lots of insulin, which must be folded in the ER. Sometimes the ER can’t handle this load
and the UPR kills these important cells, which can lead to diabetes. Parkinson’s and many other neurodegenerative
diseases are associated with extreme unfolded protein levels, which may prompt UPR-initiated
cell death in the brain. And in cancer, tumor cells can hijack the
UPR to make more ER, which helps them grow more quickly. Scientists are working to understand exactly
how Ire1 and the other UPR components work so they can harness them to regulate the UPR.
Figuring out that piece of the puzzle could be a key to treating or even curing these
diseases and more.

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