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Archive - Jan 10, 2019

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Elemental Mechanism Driving “Transcriptional Pausing”--Which Controls Gene Expression in All Living Organisms--Revealed by Work at UW-Madison; Study Also Reveals New Understanding of RNA Polymerase

A study published online on January 8, 2019 in eLife, and led by University of Wisconsin–Madison Professor of Biochemistry and Bacteriology Robert Landick, PhD, and his research team, reveals, for the first time, the elemental mechanism behind transcriptional pausing, a phenomenon that underlies the control of gene expression in all living organisms. The work also provides new understanding of the enzyme RNA polymerase, an important drug target for treating conditions such as Clostridium difficile infections and tuberculosis. The findings could ultimately improve our understanding of how certain drugs work against the enzyme and aid in actively targeting it. Gene expression is the process by which DNA is translated into all the proteins and other molecules living organisms need. Although it is a process that all introductory biology students learn about very early, scientists are still a long ways from fully understanding it. The process occurs in two steps. Transcription is the first, where RNA polymerase reads the information on a strand of DNA, which is then copied into a new molecule of messenger RNA (mRNA). In the second stage, the mRNA moves on to be processed (“translated”) into proteins by ribosomes. To help control gene expression levels, “transcriptional pausing” by RNA polymerase can occur between the two stages, providing a kind of “roadblock” where transcription may be terminated or modulated by the cell if need be. “A sequence that causes pausing of RNA polymerases in all organisms, from bacteria to mammals, halts the enzyme in a paused state from which longer-lived pauses can arise,” explains Dr. Landick. “As the fundamental mechanism of this elemental pause is not well defined, we decided to explore this using a variety of biochemical and biophysical approaches.”

Mn+2 Activates NLRP3 Inflammasome Signaling, Propagates Exosomal Release of Inflammasome Adaptor Protein ASC in Microglial Cells; Welders Exposed to Manganese-Containing Fumes Had Plasma Exosomes with More ASC Than Controls; Association with Parkinson’s

Researchers from Iowa State University (ISU) and Penn State Health Milton S. Hershey Medical Center have reported work showing that manganese activates NLRP3 inflammasome signaling and propagates exosomal release of inflammasome adaptor protein ASC [apoptosis-associated speck-like protein containing CARD)]in microglial cells. Their article was published online on January 8, 2019, in Science Signaling. At the outset, the scientists, led by senior author Anumantha G. Kanthasamy, PhD, ISU Chair of Biomedical Sciences & Eminent Scholar in Veterinary Medicine, state that chronic occupational exposure to manganese is associated with the development of Parkinson’s disease. They note that others had earlier found that exposure of primed microglial cells or mice to manganese increased NLRP3 inflammasome expression and activation. Manganese caused mitochondrial dysfunction in treated microglial cells and stimulated their release of exosomes containing the inflammasome adaptor protein ASC. The effects of manganese on inflammasome activation were sensitive to reduced endocytosis and transferable by exposure of cells to purified exosomes from ASC-sufficient cells. Similarly, serum exosomes from welders contained more ASC protein and were more inflammatory than those from normal donors, suggesting that occupational manganese exposure may increase systemic inflammasome activation due to exosome-mediated transfer of ASC. The authors note that chronic, sustained inflammation underlies many pathological conditions, including neurodegenerative diseases, and that divalent manganese (Mn2+) exposure can stimulate neurotoxicity by increasing inflammation. In the current study, the researchers examined whether Mn2+ activates the multiprotein NLRP3* inflammasome complex to promote neuroinflammation.