Feroz Papa: Saving cells from themselves

I n humans, IRE1 is central to one of three pathways that sense the presence of misfolded proteins in the ER, initiating early steps of the unfolded protein response (UPR). ER stress induces IRE1 multimerization and activation of its cytoplasmic RNase domain, which then cleaves the RNA encoding the transcription factor XBP1. This cleavage step allows XBP1's translation into protein so that it can then activate transcription of genes that help the ER adapt to the presence of unfolded proteins. But when this response is overwhelmed, IRE1 activity somehow helps tip cells into apoptosis. Feroz Papa is investigating why and how IRE1 goes from being an adaptive aide (1) to a suicide enabler (2, 3). He reasons that understanding the mechanisms that regulate IRE1 activity (1, 4) should enable the design of drugs (5) that short-circuit its maladaptive functions and give stressed cells a new lease on life. This could be important in treating the many human diseases that are driven by ER stress, such as diabetes mellitus. We called him at his offi ce at the University of California, San Fran-cisco (UCSF), to learn more. Where did you spend your childhood? I was born in Madras, India, which is now known as Chennai. My parents and I emigrated to Chicago when I was about three years old, but I returned to India and spent much of my early childhood living with my grandmother in Madras. I came back to the US when I was nine and have lived here ever since. What subjects interested you in college? My fi rst college major was electrical engineering , but I'm not exactly sure why I chose that. I wasn't particularly interested in it. My real passion around that time was classical guitar, which I'd picked up in high school. I guess I was most interested in being a classical guitarist, but I knew that I'd started way too late to be good enough to do it for a living. As a freshman at the University of Illi-nois I took a chemistry class with a fantastic teacher by the name of Steven Zumdahl. He had a program where students could apply to work in a research lab of their choice over the summers. Well, I was having so much fun at school that I decided I didn't want to come back home between my fi rst and second years and that I'd …