Deciphering of the molecular mechanism of the "unfolded protein response" (UPR) provides a wonderful example of how serendipity can shape scientific discovery. Secretory and membrane proteins begin their journey to the cell surface in the endoplasmic reticulum (ER). Before leaving the organelle, proteins are quality-controlled, and only properly folded proteins are transported onwards. The UPR detects an insufficiency in the protein-folding capacity in the ER and in the ways of a finely tuned homeostat adjusts organelle abundance according to need. If the protein-folding defect in the ER cannot be corrected, the UPR switches from a cell-protective to a cell-destructive mode and activates apoptosis in metazoan cells. Such life or death decisions position the UPR in the center of numerous pathologies, including viral infection, protein-folding diseases, diabetes, and cancer. The UPR proved to be a rich field for serendipitous discovery because the molecular machines that transmit information about insufficient protein folding and activate appropriate gene expression programs function in unusual, unprecedented ways. A key regulatory switch in the UPR, for example, is a cytoplasmic, nonconventional mRNA spicing reaction, initiated by a bifunctional transmembrane kinase/endoribonuclease.

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Walter P

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