Research Lectures at Nobel Forum
May 23, 2019, 16.30
Howard Hughes Medical Institute and Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA 94143, USA
Venue: Nobel Forum, Nobels väg 1
Host: Nico Dantuma
Targeting the Cell´s Stress Pathways for Therapeutic Benefit
From its birth in the cradle of the ribosome to its demise in the fangs of proteolytic enzymes, a protein continuously explores different folding states. In most cell compartments, molecular sensors carefully monitor protein folding and instruct down-stream effectors to take corrective actions as needed. In response, cells can make adjustments to their protein folding and degradation machineries to stay in a healthy state of homeostasis. If protein folding defects occur and cannot be corrected in a sufficient and timely manner, cells induce suicide programs. Programmed cell death is thought to protect an organism from malfunctioning rogue cells that result from an accumulation of defective protein. In various pathologies, the life/death balance can inappropriately err on either side: killing cells that would be beneficial if kept alive, or alternatively, inappropriately protecting dangerous, disease propagating cells. Studies of the regulation of proteostasis now emerge as focal points of foundational basic research that powerfully connects to a wide spectrum of unmet clinical needs.
I will discuss advances in our lab’s efforts to understand the molecular details of the unfolded protein response (UPR), a conserved signaling network that surveys the protein folding status in the endoplasmic reticulum. The UPR signals through three molecularly distinct branches. The development of small, drug-like molecules that selectively target each of the UPR’s signaling branches has opened promising new therapeutic opportunities in areas as divergent as cancer, neurodegeneration, diabetes, inflammation, aging, and cognition. As such, the UPR emerges as a prime example of the power of fundamental cell biological discoveries to address problems of immense societal impact.
Nobel Laureate Revisiting Lecture
Thursday, April 11th at 4 p.m.
Nobel Laureate in Physiology or Medicine 2013
Title: Sorting of small RNAs into extracellular vesicles secreted
by human cells
Highly purified extracellular vesicles (EVs) isolated from human cell lines display a small number of substantially (~ 1000 fold) enriched miRNAs that differ from one cell line to another. In spite of the small number of such species, no single RNA sorting sequence is evident. In order to explore the mechanism of RNA sorting, we established a cell-free reaction that reproduces the selective incorporation of synthetic, mature miRNAs (miR223 and miR122) into vesicles formed in a
reaction containing membranes and cytosol from mechanically disrupted HEK293 cells. The sorting reaction requires both membrane and cytosol and is stimulated by hydrolysable ATP and incubation at a physiologic temperature. Using biotinlyated derivatives of two different miRNAs, we found different sets of RNA binding proteins incorporated along with each species, among which the proteins Ybx1 and Lupus La are required to sort mir223 and miR122, respectively. EVs also contain more abundant major species of small RNA including full-length tRNA, Y-RNA and vault RNA, and each requires the Ybx1 protein for selective sorting into exosomes secreted by cells and into vesicles in the cell-free
reaction. The La antigen binds to both 5’ and 3’ signals on miR122 to promote packaging of the RNA into vesicles in the cell-free vesicle biogenesis reaction.
Wallenbergsalen, Nobel Forum,
Karolinska Institutet, Nobels väg 1
Professor Camilla Björkegren
Nobel Office, Nobel Forum
08-524 878 00,