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Profile of Peter Novick PROFILE PROFILE Profile of Peter Novick Sandeep Ravindran Science Writer There was a time in graduate school when a combination of yeast genetics and cell Peter Novick wasn’tsureifhisresearch biology, he has spent his career investigating wouldleadanywhere.Asagraduatestudent the tightly regulated mechanisms involved in in cell biologist Randy Schekman’s laboratory intracellular transport. For his contributions at the University of California at Berkeley, to our understanding of this fundamental Novick had been using a genetic approach physiological process, Novick was elected to to understand the yeast secretory pathway, the National Academy of Sciences in 2013. responsible for moving proteins out of the “In his own lab, first at Yale and now at cell. Now a professor at the University of UC San Diego, Peter launched a brilliant in- California, San Diego, Novick says it was only dependent career with the discovery that a when he identified a mutant in which vesicles protein called Sec4 encodes a small GTP- piledupinsidethecell,showingthatithad binding protein, the first of three dozen so- a defective secretory pathway, that he knew called Rab proteins that we now know con- he had made a breakthrough. “That con- trol the targeting of transport vesicles to all vinced me. Before then I wasn’tsureifI the many destinations in the cell,” says had a thesis project, afterwards it was pretty Schekman. “On the strength of this work clear I did,” he says. and much more in subsequent years, he It turned out that Novick had a lot more was elected to the National Academy of Sci- than a thesis project. His graduate work ences, an honor that was in my opinion long paved the way for Schekman’sdetailedanal- overdue,” he says. ysis of the secretory pathway, work for which Peter Novick. Schekman shared the 2013 Nobel Prize in Identifying Genes Involved in Secretion Physiology or Medicine. “Peter Novick was When he went to graduate school at Berkeley, sec1-1 ” instrumental in starting our genetic approach Novick was interested in studying cell mem- than , it was just a beautiful mutant, to the secretory pathway in yeast,” says branes and membrane proteins, but “there Novick says. sec1-1 Schekman. “Already as a first year graduate weren’t too many labs studying membranes Novick studied the mutant in detail “ student, he showed great skill and devised the at that time,” he says. Then he met Randy and found an unusual property: These guys screen and a selection procedure that allowed Schekman. “He was a brand new assistant were far, far more dense than any wild-type ” “ ’ us to isolate the first mutant, sec1-1,and professor and he suggested the possibility of cells, he says. It makes sense. If you re not within another year, mutations representing using genetics to study membranes,” Novick expanding the surface area of the plasma ’ 23 genes that defined the major stages in says. Novick enjoyed genetics, so “the idea of membrane, the volume of the cell can tin- the secretory pathway,” he says. doing genetics on membranes was very ap- crease, but the cells were still metabolically In eukaryotic cells, such as yeast and higher pealing,” he says, and “It turned out to be a active and making RNA and protein, so they organisms, the secretory pathway transports really good match.” got very dense,” Novick says. proteins from the endoplasmic reticulum (ER), In Schekman’s laboratory, Novick set out Novickwasabletousethefactthatthe an organelle where the proteins are synthe- to make yeast mutants in which secretion mutants with defective secretion were dense sized, to the Golgi apparatus, a cellular com- was blocked. When he selected for mutants to enrich them 100-fold over WT cells. Over partment that serves as a sorting station. that had a defective secretion system, “Igot a couple of different experiments, he isolated From the Golgi, the proteins then move to this excellent sec1-1 mutant, and I spent quite more than 200 secretory mutants, which later the cells’ plasma membrane. The latter step a bit of time studying it,” Novick says (1). defined 23 genes involved in the secretory involves transporting the proteins in vesicles Blocking secretion is often lethal to cells, so pathway (2). that fuse with the plasma membrane and re- all of the mutants Novick got were temper- Novick was confident that these secretory lease proteins to the outside of the cell. The ature sensitive, including sec1-1. pathway genes represented a conserved eu- regulation of such intracellular trafficking is “At 25 degrees [Celsius] it was essentially karyotic mechanism. “We didn’tknowfor relevant to many human diseases, including like wild-type cells, and then within minutes sure how general these pathways would be, cancer and diabetes. Understanding how of shifting to 37 degrees [Celsius], secretion but there’s general optimism that things yeast secretes proteins has also been used was blocked,” he says. “It just was like turn- evolve once, and if they work, you keep in biotechnology to produce proteins such ing off a light switch,” Novick says. “The them,” he says. This view was reinforced as insulin. mutant cell became packed with vesicles that ’ Novick says his graduate work led to his couldn t get out. In terms of a graphic, dra- fi ” This is a Pro le of a recently elected member of the National continued interest in teasing apart the many matic experiment, that takes the cake, he Academy of Sciences to accompany the member’s Inaugural Article components of the secretory pathway. Using says. “Idon’tthinkIevergotabettermutant on page 19995 in issue 50 of volume 110. www.pnas.org/cgi/doi/10.1073/pnas.1321513110 PNAS | January 7, 2014 | vol. 111 | no. 1 | 3–4 Downloaded by guest on October 1, 2021 when he found that the secretory pathway he the end of the secretory pathway encoded a few proteins are showing up that seem to fit described was strikingly similar to one pre- proteins that were all part of the same com- that paradigm,” he says. viously described in pancreatic cells (3, 4). plex, which could associate with membranes. Novick’s Inaugural Article further eluci- “In my thesis I put these genes on a map, “This ultimately became the complex that we dates the regulation of Sec2 and the final and that map looked strikingly like the se- call the exocyst,” Novick says. Two additional stages of the secretory pathway (9). Novick cretory pathway in pancreatic acinar cells. components, Exo70 and Exo84, were identi- found that phosphorylation of a binding site They both involved transport from the ER to fied biochemically. on Sec2 switches Sec2 from binding Ypt32 to Golgi to secretory vesicles to the cell surface, Novick showed that the exocyst complex binding one of the subunits of the exocyst, with energy requirements at each of those acted as a downstream effector of Sec4 to Sec15. When Sec2 is bound to Ypt32, it is stages,” Novick says. “Considering how dif- direct the fusion of secretory vesicles to the part of the cascade of Rab activation. How- ferent yeast is from the pancreas, I just plasma membrane and was one of the first ever, when Sec2 switches to binding Sec15, it thoughtthatwasgreat,” he says. Rab effectors found. Novick also found that can start a positive feedback loop where Sec2 However, finding the genes involved in the one of the other Sec proteins, Sec2, interacted activates Sec4, Sec4 recruits Sec15, Sec15 is secretory pathway was only a starting point. with Sec4 and catalyzed Sec4’sexchangeof still bound to Sec2, and Sec2 can now reac- “ There was tremendous promise in that we GDP for GTP, a form of cellular energy tivate Sec4. fi had identi ed all these genes, but when I left currency similar to ATP. Sec2 was one of the “Our thought is that Sec2 is initially fi fi graduate school we still had no idea what any rst Rab exchange proteins identi ed. Sec4 recruited in a nonphosphorylated state by ” “ of the gene products were doing, he says. It thus acted as the Rab GTPase controlling the Ypt32, and as the vesicle is reaching the was a black box, with a lot of gene products, exocyst, and Sec2 as the exchange protein plasma membrane, phosphorylation acts as ’ ” but we didn tknowwhattheywere, that activated Sec4. a regulatory switch that causes Sec2 to now Novick says. ’ Coordinating the Secretory Pathway bind Sec15 and start this feedback loop that s Hunt for Gene Function ’ required to prepare the vesicle for fusion with Novick s next goal was to determine how the ” “ ’ In 1985, Novick started his own laboratory at various components of the secretory pathway the plasma membrane, he says. It sallpart Yale University and decided to use the rap- could be coordinated. His laboratory identi- of the circuitry, and this is a switch that idly evolving field of molecular genetics to fied an interaction between Sec2 and a Rab switches from one type of circuit to a differ- ” investigate what the different genes in the GTPase called Ypt32 that acted just upstream ent type, Novick says. ’ secretory pathway were doing. “Yeast trans- of Sec4. Sec2 was found to bind to the acti- Novick states that researchers under- fi formation had been developed, and it became vated form of Ypt32 as an effector (7). As standing of vesicle traf cking has come a long “ clear that we could get at the genes without Sec2 also bound to Sec4 as an exchange waysincehewasingraduateschool. Randy having to purify proteins,” he says (5). protein, this led to the idea of a “cascade Schekman winning the Nobel Prize together Novick decided to focus on the end of the model,” where one Rab binds to the exchange with James Rothman and Thomas Sudhof secretory pathway, involving the transport of protein that activates the next Rab.
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