Showing defective proteins the door

Each of our cells contains an intricate factory for making proteins. Any assembly line with many steps produces some glitches, so it’s important to check the quality of the end products. For proteins, this includes verifying that they have been folded into a precise shape that enables them to interact with other molecules and carry out their functions. Any failure in quality control can quickly lead to an accumulation of misfolded proteins that malfunction and cause serious diseases. Thomas Sommer’s lab has now identified a molecule that helps recognize defective molecules and eject them from a cellular compartment called the endoplasmic reticulum (ER), an important step in their degradation. The work appears in the January 16 issue of Nature Cell Biology.

  A possible model for the transport of misfolded proteins (red) from the ER compartment (top) to the cell cytoplasm (bottom): the proteins are recognized by proteins such as Hrd3/Yos9 and are then transported through a flexible channel in the membrane, composed of Der1 (green) in conjunction with other molecules. Outside Hrd1 tags them with ubiquitins, which mark the proteins for destruction.

“The ER is involved in the production of proteins that will be secreted from the cell or embedded in membranes,” Thomas says. “The ER contains the machinery to fold these proteins, but not to break them down if they turn out to have defects. That happens outside the compartment, in the cell cytoplasm.”

To get there they must pass through a specialized channel in the membrane surrounding the ER. Such channels are usually composed of protein “doorkeepers” that check a molecule before letting it through, then hand it off to partners on the other side.

What happens then is called ER-associated protein degradation (ERAD), a process that is fairly well understood thanks to previous work by Thomas’ group and many others. The channel itself, however, remained unknown. Postdoc Martin Mehnert and senior scientist Ernst Jarosch set out to look for it.

“Some of the components of ERAD are lodged in the membrane. It’s likely that they are in direct contact with the channel, at least part of the time,” Ernst says. “So we began looking at molecules that associate with the ERAD machinery.”

Some proteins in the membrane have regions extending into the ER; others dangle into the cytoplasm. A first step in ERAD is to draw them together into a machine that can identify misfolded molecules inside and mark them for destruction in the cytoplasm. One of the proteins, Hrd1, has a “workbench” outside that helps glue ubiquitins onto the proteins, signaling that they should be destroyed.

“We knew that a protein called Usa1 helps connect the other components to Hrd1,” Martin says. “It also connects Hrd1 to another membrane protein called Der1, whose functions were unknown.”

A few years ago Thomas and Ernst speculated that Der1 might help recognizing proteins that needed to be removed. It might even be involved in transporting them outward – a possibility suggested by its architecture. Der1 threads back and forth through the membrane, like a stitch sewn through a bit of cloth. It’s a structure frequently found in proteins that make up membrane channels.

Is Der1 the channel? Stay tuned – the lab isn’t willing to go that far, just yet. “But we do provide strong evidence that Der1 participates in extracting proteins from the ER,” Thomas says. “We know that it weakly links up to aberrant molecules. We’ve shown that if you alter Der1, at least some misfolded proteins can’t escape. Multiple copies of Der1 assemble in the membrane, which is a typical feature of channels, and they bind to other molecules that are essential in transporting proteins to the cytoplasm. They may join other ERAD components to create a flexible channel to eject the molecules and hand them over to Hrd1.”

- Russ Hodge

Highlight Reference:

Mehnert M, Sommer T, Jarosch E. Der1 promotes movement of misfolded proteins through the endoplasmic reticulum membrane. Nat Cell Biol. 2014 Jan;16(1):77-86. doi: 10.1038/ncb2882

Link to the original paper