Allyson F. O'Donnell

  • Assistant Professor
  • Protein Trafficking

Contact

A312 Langley Hall
5th & Ruskin Ave.
Pittsburgh, PA 15260

Nearly half of all prescription drugs alter G-protein coupled receptor (GPCR) signaling, including treatments for asthma, hypertension, neurodegenerative disorders and depression. β-arrestins are critical regulators of GPCRs: they act as trafficking adaptors to control GPCR endocytosis and impede G-protein signaling. β-arrestins are themselves therapeutic targets, highlighting the clinical importance of understanding arrestin function. However, β-arrestins are only a small branch of the larger arrestin family that includes the widely-conserved but functionally uncharacterized α-arrestins, the primary focus of our research. Our work has shown that α-arrestins, like β-arrestins, regulate GPCR signaling, but also operate in unexpected trafficking pathways, including endosomal recycling and clathrin-independent endocytosis. Using Saccharomyces cerevisiae as a model, our research has shown that α-arrestins interact with signaling regulators, including kinases and phosphatases, to selectively direct trafficking of specific transmembrane cargo proteins, presumably by promoting their ubiquitination and packaging into vesicles (Figure 1), and have begun to define the molecular mechanisms underlying α-arrestin-mediated trafficking. All of the α-arrestin-interacting partners identified in yeast are conserved. Our research will apply insights gained in yeast to initiate studies on the relatively unstudied mammalian α-arrestins.

The study of α-arrestins is in its infancy. There are still many unanswered questions about arrestin biology: What are the initial signaling cues that regulate α-arrestin trafficking? How are specific cargo proteins recognized? How does the arrestin-cargo interaction direct a protein cargo to its final destination? Our research employs molecular, biochemical, genetic and advanced microscopy methods to address these fundamental questions about arrestin function in yeast to expand our understanding of GPCR signaling and protein trafficking.

E-mail Lab

Hager, N.A., C.J. Krasowski, T.D. Mackie, A.R.

Hager, N.A., C.J. Krasowski, T.D. Mackie, A.R. Kolb, P.G. Needham, A.A. Augustine, A. Dempsey, C. Szent-Gyorgyi, M.P. Bruchez, D.J. Bain, A.V. Kwiatkowski, A.F. O’Donnell and J.L. Brodsky. Select α-arrestins control surface abundance of the mammalian Kir2.1 potassium channel in a yeast model. J. Biol. Chem. (2018) 293:11006-11021

Mackie, T.D., B.Y. Kim, A.R. Subramanya, D.J. B

Mackie, T.D., B.Y. Kim, A.R. Subramanya, D.J. Bain, A.F. O’Donnell, P.A. Welling, and J.L. Brodsky. The endosomal trafficking factors CORVET and ESCRT suppress plasma membrane residence of the renal outer medullary potassium channel (ROMK). J. Biol. Chem. (2018) 293: 3201-3217

Chandrashekarappa, D.G., R. R. McCartney, A.F.

Chandrashekarappa, D.G., R. R. McCartney, A.F. O’Donnell, and M.C. Schmidt. (2016) The β-subunits of yeast AMP-activated protein kinase direct substrate specificity in response to alkaline stress. Cell Signaling, 28(12):1881-1893.

Prosser, D.C., K. Wrasman, T. K. Woodard, A. F.

Prosser, D.C., K. Wrasman, T. K. Woodard, A. F. O’Donnell, and B. Wendland. (2016) Applications of pHluorin for quantitative, kinetic, and high-throughput analysis of endocytosis in budding yeast. Journal of Visual Experimentation, 116:e54587, doi:10.379/54587.

Prosser, D.C., A.E. Pannunzio, J. Brodsky, J. T

Prosser, D.C., A.E. Pannunzio, J. Brodsky, J. Thorner, B. Wendland, and A.F. O’Donnell. (2015) Alpha-arrestins participate in cargo selection for both clathrin-independent and clathrin-mediated endocytosis. Journal of Cell Science, 128(22):4220-34.    

O’Donnell, A.F., R. R. McCartney, D. G.

O’Donnell, A.F., R. R. McCartney, D. G. Chandrashekarappa, B. Zhang, J. Thorner, and M.C. Schmidt. (2015) 2-Deoxyglucose impairs yeast growth by stimulating Snf1-regulated and α-arrestin-mediated trafficking of hexose transporters 1 and 3 in Saccharomyces cerevisiae. Molecular and Cellular Biology, 35(6):939-55.  

C.G. Alvaro, A.F. O’Donnell*, D.C. Pross

C.G. Alvaro, A.F. O’Donnell*, D.C. Prosser, A.A. Augustine, A. Goldman, J. Brodsky, M.S. Cyert, B. Wendland, and J. Thorner. (2014) Specific α-arrestins negatively regulate Saccharomyces cerevisiae pheromone response by down-modulating the G-protein coupled receptor Ste2. Molecular and Cellular Biology 34(14):2660-81.

Hecht, K.A., A.F. O’Donnell, and J.L. Brodsky.

Hecht, K.A., A.F. O’Donnell, and J.L. Brodsky. The proteolytic landscape of the yeast vacuole.  Cell. Logistics (2014) 4(1):e28023

O’Donnell, A.F., L. Huang, J. Thorner, a

O’Donnell, A.F., L. Huang, J. Thorner, and M.S. Cyert. (2013) A calcineurin-dependent switch controls the trafficking function of α-arrestin Aly1/Art6. The Journal of Biological Chemistry. 288 (33): 24063-24080

O’Donnell, A.F. (2012) The running of th

O’Donnell, A.F. (2012) The running of the Buls: Control of permease trafficking by α-arrestins Bul1 and Bul2. Molecular and Cellular Biology 32 (22): 4506-09.

Stevens, J.R., A.F. O’Donnell, T.E. Perr

Stevens, J.R., A.F. O’Donnell, T.E. Perry, J.R. Benjamin, C.A. Barnes, G.C. Johnston, and R.A. Singer. (2011) FACT, the Bur kinase pathway, and the histone co-repressor HirC have overlapping nucleosome-related roles in yeast transcription elongation. PLoS One 6 (10): e25644.

Minear, S., A.F. O’Donnell, G. Giaever,

Minear, S., A.F. O’Donnell, G. Giaever, C. Nislow, T. Stearns, and M.S. Cyert. (2011) Curcumin inhibits growth of Saccharomyces cerevisiae through iron chelation. Eukaryotic Cell 10 (11): 1574-81.

Piña, F.J., A.F. O’Donnell, S. Pagant, H

Piña, F.J., A.F. O’Donnell, S. Pagant, H.L. Piao, J.P. Miller, S. Fields, E.A. Miller, and M.S. Cyert. (2011) Hph1 and Hph2 are novel components of the Sec63/Sec62 posttranslational translocation complex that aid in vacuolar proton ATPase biogenesis. Eukaryotic Cell 10 (1): 63-71.

O’Donnell, A.F., A. Apffel, R.G. Gardner

O’Donnell, A.F., A. Apffel, R.G. Gardner, and M.S. Cyert. (2010) a-arrestins Aly1 and Aly2 regulate intracellular trafficking in response to nutrient signaling. Molecular Biology of the Cell 21 (20): 3552-3566. (Highlighted publication in MBoC)

O’Donnell, A.F., J.R. Stevens, R. Kepkay

O’Donnell, A.F., J.R. Stevens, R. Kepkay, C.A. Barnes, G.C. Johnston, and R.A. Singer. (2009) New mutant versions of yeast FACT subunit Spt16 affect cell integrity. Molecular Genetics and Genomics 282 (5): 487-502.

O’Donnell, A.F., N.K. Brewster, J. Kurni

O’Donnell, A.F., N.K. Brewster, J. Kurniawan, L.V. Minard, G.C. Johnston, and R.A. Singer. (2004) Domain organization of the yeast histone chaperone FACT: the conserved N-terminal domain of FACT subunit Spt16 mediates recovery from replication stress. Nucleic Acids Research 32 (19): 5894-5906.

O’Donnell, A.F., S. Tiong, D. Nash, and

O’Donnell, A.F., S. Tiong, D. Nash, and D.V. Clark (2000) The Drosophila melanogaster ade5 gene encodes a bifunctional enzyme for two steps in the de novo purine synthesis pathway. Genetics 154 (3): 1239-1253.

Dr. Allyson O'Donnell joined the department in 2018. Allyson is also a member of the Center for Protein Conformational Diseases at the University of Pittsburgh ( http://www.proteindiseasecenter.pitt.edu/about-our-center), an Ambassador for the American Society for Cell Biology and a mentor for the Science Research Outreach Program at Taylor Allderdice High School.

Dr. O'Donnell received her B.S. degree in Biochemistry and M.S. degree in Biology from the University of New Brunswick (Canada). During her Masters’ thesis work she identified genes needed for de novo purine biosynthesis in Drosophila melanogaster and characterized the developmental defects associated with mutations in these genes. Dr. O'Donnell went on to receive her Ph.D. in Biochemistry & Molecular Biology from Dalhousie University (Canada) where she studied the role of the FACT histone chaperone complex in chromatin remodeling.

During her post-doctoral research at Stanford University and the University of California, Berkeley Dr. O'Donnell began her research on a previously unstudied class of protein trafficking adaptors, now referred to as the α-arrestins. Her research has shown that α-arrestins regulate trafficking of G-protein coupled receptors, but also operate in unexpected trafficking pathways, including endosomal recycling and clathrin-independent endocytosis. Using Saccharomyces cerevisiae as a model, she has identified α-arrestin interactions with signaling regulators, cargos and vesicle coat proteins, and has begun to define the molecular mechanisms underlying α-arrestin-mediated trafficking. Her research applies insights gained in yeast to target studies on the relatively unstudied mammalian α-arrestins.