Christopher Nicchitta, Ph.D. (University of Pennsylvania)
Professor, Department of Cell Biology
CMB Program, Comprehensive
436A Nanaline Duke Bldg., Box 3709
Duke University Medical Center
Durham, NC 27710
Our lab studies the cellular architecture and regulation of protein synthesis, with a primary focus on understanding how cells regulate both the subcellular location and temporal dynamics of protein synthesis. Here, we focus on mRNA localization. mRNA localization is a primary mechanism used by all eukaryotic cells to regulate the spatiotemporal component of gene expression - where and when an mRNA is translated to yield its encoded protein. Such regulation is critical for proper control of cell dynamics, cell signaling and cell division. Of the many 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 is distinguished by its magnitude (ca. 30-40% of the mRNA transcriptome is localized to the ER) and temporal demands - all newly exported mRNAs undergo selection for translation in the cytosol and/or ER compartments. In studying this question, we use a broad array of tools drawn from biochemistry, cell biology, genomics, and computational biology, and are focusing on several related themes that define this central question. Primarily, we are working to establish the rules that govern the association of mRNAs with the ER. One mechanism, in which a signal in the encoded protein leads to recruitment to the ER, has been described. The identification and characterization of additional pathways leading to ER enrichment remains a central and largely unanswered question. We are also investigating how mRNAs might directly bind to the ER independently of their association with ribosomes. In a recent paper from our lab, we have demonstrated that the mRNAs that encode the resident proteins of the endomembrane system (nuclear envelope, ER, Golgi, lysosomes, peroxisomes and plasma membrane) are localized to discrete domains of the ER and undergo direct binding interactions with components of the ER membrane components. We are keenly interested in understanding what signals and signal binding protein(s) direct this critical subset of mRNAs to this discrete subcellular location in the cell and how such localization contributes to the biogenesis of cell structure and regulation of cell function.
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.