Bernasconi et al. clarify how mammalian cells remove misfolded ER proteins for disposal—how a particular protein exits depends on its ER location.
Newly made proteins idle in the ER while they fold into shape. Proteins that make a mistake during the process are usually expelled from the ER and destroyed by the proteasome. Several protein complexes embedded in the ER membrane can remove these rejects, and evidence from yeast suggests that the location of the error within the protein determines which complex handles its elimination. For example, proteins with flaws in their cytoplasmic section are shunted through the complex that contains the enzyme DOA10. But if the damage falls in the section of the protein protruding into the ER lumen, the HRD1-containing complex clears the damaged molecule. Bernasconi et al. wanted to determine what happens in mammals, where the situation is hazy.
The researchers tested how mammalian cells dispose of the enzyme β-secretase (BACE) and CD3-δ, which is part of the T cell receptor. Both proteins had folding errors in the lumenal region, which in yeast would mean the same pathway would expel them from the ER. But Bernasconi et al. found that another factor was important in mammalian cells: whether the protein was soluble or connected to the ER membrane. CD3-δ normally carries a membrane-tethering segment. Removing this anchor made the protein soluble in the ER and changed which pathway was used for disposal. Deleting the tether from BACE also altered its exit route.
Bernasconi et al. also showed that two mysterious proteins serve as shuttles, delivering faulty soluble proteins to the ER membrane for disposal. The shuttles didn't transport tethered proteins, however—membrane-anchored proteins are already near the disposal complexes and don't need to be fetched. A key question that needs to be answered, the researchers say, is which protein channel ushers the misfolded proteins through the ER membrane.
