Christopher Nicchitta, Ph.D. (University of Pennsylvania)
Professor, Department of Cell Biology
Associate Dean for Research Training
CMB Program, Comprehensive Cancer Center
436A Nanaline Duke Bldg., Box 3709
Duke University Medical Center
Durham, NC 27710
Our laboratory studies the cellular architecture and regulation of protein synthesis, with the goal of understanding how cells regulate the subcellular organization and temporal dynamics of protein synthesis. We focus on mRNA localization - the process by which cells control where and when a protein is synthesized by localizing its mRNA to a discrete location(s) in the cell. Such regulation is critical for many aspects of cell dynamics, cell signaling and cell division. Of the diverse mRNA localization phenomena that have been identified to date, the most prominent is mRNA localization to the endoplasmic reticulum (ER). mRNA localization to the ER operates on an unusually large scale (essentially the entire mRNA transcriptome is partially represented on the ER, with those mRNAs encoding secretory and membrane proteins being highly ER-enriched), and continuously– all newly exported mRNAs undergo selection for translation in the cytosol and/or the ER compartments.
We use a broad array of experimental approaches - biochemistry, cell biology, genomics, and computational biology - and are focusing on several related themes. First, we are working to identify the mRNA-encoded signals used to target mRNAs to the ER as well as the cellular factors that recognize these signals. One mechanism, in which a signal in nascent secretory and membrane proteins directs mRNA recruitment to the ER, has been previously described. It is clear though that there are multiple pathways that direct mRNAs to the ER, including pathways that direct cytosolic and nucleoplasmic protein-encoding mRNAs to the ER. We are also investigating how, once localized, mRNAs are anchored to the ER membrane. In a recent study, we reported that the cohort of mRNAs encoding organelle resident proteins (e.g., nuclear envelope, ER, Golgi, lysosomes, peroxisomes) are localized to the ER and directly anchored to components of the ER membrane. We are very interested in understanding what anchoring signals and anchoring signal binding protein(s) mediate this process and how direct mRNA anchoring contributes to cell structure and function.
In parallel efforts, we discovered that mRNA translation is under distinct regulatory control in the cytosol and ER compartments, with translation being 3-5 fold more efficient on the ER. These differences are substantial and suggest that mRNA localization to the ER may represent an important post-transcriptional gene expression mechanism. To gain insight into the mechanisms and factors responsible for the compartmental regulation of mRNA translation we are using traditional biochemical approaches (pulse-labeling, cell fractionation, immunoprecipitation, proteomics) as well as genomic approaches (ribosome footprinting, deep sequencing).
Epple LM, Dodd RD, Merz AL, Dechkovskaia AM, Herring M, Winston BA, Lencioni AM, Russell RL, Madsen H, Nega M, Dusto NL, White J, Bigner DD, Nicchitta CV, Serkova NJ, Graner MW (2013) Incuction of the unfolded protein repsonse drives enhanced metabolism and chemoresistance in glioma cells. PLoS One. 8(8):e73267
Lacsina JR, Marks OA, Liu X, Reid DW, Jagannathan S, Nicchitta CV (2012) Premature translational termination products are rapidly degraded substrates for MHC class I presentation. PLoS One. 7(12):e51968
Lampson BL, Pershing NL, Prinz JA, Lacsina JR, Marzluff WF, Nicchitta CV, MacAlpine DM, Counter CM (2013) Rare codons regulate KRas oncogenesis. Curr Biol. 23(1):70-5
LaMonte G, Philip N, Reardon J, Lacsina JR, Majoros W, Chapman L, Thornburg CD, Telen MJ, Ohler U, Nicchitta CV, Haystead T, Chi JT (2012) Translocation of sickle cell erythrocyte microRNAs into Plasmodium falciparum inhibits parasite translation and contributes to malaria resistance. Cell Host Microbe. 12(2):187-99
Huang QQ, Koessler RE, Birkett R, Dorfleutner A, Perlman H, Haines GK 3rd, Stehlik C, Nicchitta CV, Pope RM (2012) Glycoprotein 96 perpetuates the persistent inflammation of rheumatoid arthritus. Arthritis Rheum. 64(11):3638-48
Duerfeldt AS, Peterson LB, Maynard JC, Ng CL, Eletto D, Ostrovsky O, Shinogle HE, Moore DS, Argon Y, Nicchitta CV, Blagg BS (2012) Development of a Grp94 inhibitor. J Am Chem Soc. 134(23):9796-804
Reid DW, Nicchitta CV (2012) The enduring enigma of nulear translation. J Cell Biol. 197(1):7-9
Reid DW, Nicchitta CV. (2012) Primary role for endoplasmic reticulum-bound ribosomes in cellular translation identified by ribosome profiling. J Biol Chem. Feb 17; 287(8):5518-27.
Chen Q, Jagannathan S, Reid DW, Zheng T, Nicchitta CV. (2011) Hierarchical regulation of mRNA partitioning between the cytoplasm and the endoplasmic reticulum of mammalian cells. Mol Biol Cell. 22(14):2646-58.
Jagannathan S, Nwosu C, Nicchitta CV. (2011) Analyzing mRNA localization to the endoplasmic reticulum via cell fractionation. Methods Mol Biol. 2011;714:301-21.