Membrane and secretory proteins are imported cotranslationally into an intracellular membrane network known as the endoplasmic reticulum (ER). Here the newly synthesized proteins fold and assemble, but, if the proteins do not fold correctly, they are sequestered in the ER and subsequently degraded. When cells are subject to stress, such as high temperature, the number of proteins misfolding and thus requiring disposal increase, and a cellular quality control mechanism—the unfolded protein response (UPR) pathway—is recruited.
Bertolotti et al. examined the UPR pathway in mammalian cell lines and discovered that two ER-resident transmembrane kinases interact reversibly with the folding chaperone BiP. When BiP is particularly busy binding to unfolded protein substrates, the kinases are freed to form activated complexes, which then trigger the synthesis of more ER folding factors. Travers et al. used DNA microarrays to look at the relationship between the UPR pathway and ER-associated degradation and found that the two pathways were coordinately regulated, even in unstressed cells.—SMH
Nature Cell Biol.2, 326 (2000); Cell101, 249 (2000).