Study identifies chemical in diet that determines a honey bee’s caste
A closer look at how honey bee colonies determine which larvae will serve as workers and which will become queens reveals that a plant chemical, p-coumaric acid, plays a key role in the bees’ developmental fate.
The study, reported in the journal Science Advances, shows that broad developmental changes occur when honey bee larvae – those fated to be workers – are switched from eating royal jelly (a glandular secretion) to a diet of jelly that includes honey and beebread (a type of processed pollen).
Beebread and honey contain p-coumaric acid, but royal jelly does not. Queens feed exclusively on royal jelly. Worker bees known as nurses feed the larvae according to the needs of the hive.
Experiments revealed that ingesting p-coumaric acid pushes the honey bee larvae down a different developmental pathway from those fed only royal jelly. Some genes, about a third of the honey bee genome, are upregulated and another third are downregulated, changing the landscape of proteins available to help fight disease or develop the bees’ reproductive parts.
“Consuming the phytochemical p-coumaric acid, which is ubiquitous in beebread and honey, alters the expression of a whole suite of genes involved in caste determination,” said University of Illinois entomology professor and department head May Berenbaum, who conducted the study with research scientist Wenfu Mao and cell and developmental biology professor Mary Schuler. “For years, people have wondered what components in royal jelly lead to queen development, but what might be more important is what isn’t in royal jelly – plant chemicals that can interfere with development.”
“While previous molecular studies have provided simple snapshots of the gene transcript variations that are associated with the exposure of insects to natural and synthetic chemicals, the genomics approaches used in this study offer a significantly more complex perspective on the biochemical and physiological processes occurring in plant-insect interactions,” Schuler said.
The USDA Agricultural and Food Research Initiative supported this research.
Story by Diana Yates, Life Sciences Editor, Illinois News Bureau
Photo by Terry Harrison, U. of I. beekeeper
Ann Zielinski, MCB’s Associate Director for Business Affairs, has been awarded the SPaRC Career Achievement Award.
Coming from a research background in Plant Physiology, Biochemistry and Endocrinology, Ann began her career at Illinois in the lab of I.C. “Gunny” Gunsalus, managing his research laboratory as well as his new endeavors as Assistant Secretary General of the United Nations. Over the years, Ann’s math and financial abilities were quickly recognized and grant expenditure management was added to her responsibilities. Importantly, Ann has been responsible for MCB’s performance in audits from the University, State and Federal agencies. She serves tirelessly on campus and college level administrative committees and is the 'go-to' person for advice and strategic vision. Her long-term dedication to excellence and high standards has served the School and Campus exceedingly well. “Ms. Zielinski is clearly an outstanding asset to the Illinois research enterprise,” said Dr. Stephen Sligar, director of the School of Molecular and Cellular Biology. “Her long-term dedication to excellence and high standards has served the school and campus exceedingly well. Her service is most appropriately rewarded by receipt of the SPaRC Career Achievement Award.” Sponsored Projects and Research Compliance (SPARC) is a comprehensive working group exclusively devoted to the management and administration of sponsored projects and open to all who wish to participate. SPaRC is supported by the Office of the Assistant Vice President for Business & Finance and the Office of the Vice Chancellor for Research. SPaRC Career Achievement Awards recognize professionals who have supported the field of research administration at Illinois for a minimum of ten years and have demonstrated a significant positive impact upon the support of Illinois research administration.
Posted August 24, 2015
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Andrew Belmont: Influencing a generation of chromatin biology
As a postdoc studying chromosomal structure with David Agard and John Sedat in the late 1980s, Andrew Belmont had observed intriguing ultrastructural details in interphase nuclei. “We’d see large-scale fibers about 100 nanometers thick, and then there’d be a 10- to 30-nanometer-thick fiber looping out, which we thought might represent an active gene,” says Belmont. “However, we couldn’t rule out that these features were simply artifacts of fixation or sample preparation because we couldn’t identify the region that we were looking at.”
At the time, the only method available to identify a specific chromosomal region was in situ hybridization, in which a radioactive or fluorescently labeled nucleotide probe is annealed to complementary DNA or RNA sequences that have been denatured by chemicals or heat. The technique, first described in 1969, enabled major advances in cytogenetics and genomic mapping. But it wasn’t suited to the application Belmont had in mind.
“One of the first experiments I did in my own lab was to perform a mock in situ hybridization and then take the sample to the electron microscope. I saw the chromatin structure was completely trashed at the ultrastructural level,” recalls Belmont. His group needed a way to label specific chromatin structures in cells that also preserved DNA ultrastructure. The approach they devised was described in a 1996 paper published in JCB.
“It seemed like a crazy idea at the time, and I was concerned it wouldn’t even work.”
The paper unveiled a genetic construct containing 256 lac operator repeats that, once integrated into a cell’s DNA, could be recognized by the lac repressor protein in both fixed and living cells. The site of lac repressor binding could then be visualized by indirect immunofluorescence or via fusion to the recently discovered green fluorescent protein. In mammalian cells, a single copy of the 256 repeat construct was sufficient to identify the site of its integration, which appeared under the light microscope as a tiny dot in the cell’s nucleus. Importantly, however, amplification of the inserted repeat also granted insight into chromosomal structure.
“We showed that different amplified regions fold in characteristic patterns,” notes Belmont. These patterns corresponded to whether the tag had integrated at open versus condensed chromosome regions. “We could observe large-scale chromatin fibers under a light microscope, then take them straight to the electron microscope and identify those fibers at the ultrastructural level by immunogold staining”—thus confirming that the large-scale chromatin fibers Belmont had previously seen in fixed extracted cells actually exist in live cells.
Finally, through collaboration with Andrew Murray’s lab, the researchers showed that it was possible to insert a lac operator tag at a specific site in the yeast genome. This made it possible to follow dynamics of specific chromosomal loci in living cells.
Their approach was successful, but Belmont admits he’s amazed it even got off the ground. “I kept outlining the project to prospective graduate students and no one would bite. It seemed like a crazy idea at the time, and I was concerned it wouldn’t even work.” It wasn’t clear the lac repressor would recognize the operator motif once it was assembled on nucleosomes, or that repressor binding would be detectable by the fluorescent probes and microscope cameras then available.
“It is often the case that ideas that look good on paper totally fail when confronted with the reality of biology,” agrees Carmen Robinett, first author on the paper. “Yet at every step, things just worked.”
Belmont says the credit for that goes to Robinett. “I didn’t even own a gel box at the time we began the work. I had no experience with any kind of recombinant DNA work, but Carmen basically came to the lab as a master’s student, and planned and executed what in retrospect was a really difficult cloning project to make the lac operator repeat construct. She generated the cell lines containing amplified chromosome regions with the inserts, and even established Drosophila lines carrying the repeats. But then she had to leave the lab to start her PhD degree in Berkeley, and the project languished for a year or more before my department head, Rick Horwitz, rescued me with funding for a technician.”
Belmont actually attributes his successful tenure application to this paper and the work it enabled, which includes investigations into fundamental questions about chromatin structure and localization.
Others have found it quite useful as well. “Their proof-of-principle application was inspirational,” says former JCB Editor-in-Chief Tom Misteli. “It spawned an entire tool kit for tethering proteins to chromatin and for labeling, immobilizing and targeting chromatin regions. The system has generated insights into problems ranging from DNA repair and chromatin dynamics to gene positioning and nuclear body formation.”
Original "From the Archive" article by Caitlin Sedwick, published in JCB here.
Dr. Sligar, Director of the School of MCB, has been awarded the Herbert A. Sober Lectureship
Dr. Sligar’s lab has been exploring how to reveal the structure and function of membrane proteins through the use of nanotechnology. Membrane proteins have been historically difficult to study due to many of the current biophysical and chemical techniques applicable to soluble enzymes failing to deal with insoluble aggregates. The emergence of nanotechnology could eliminate challenges faced by researchers during the solubilization of membrane proteins and allow for the study of membrane proteins from a mechanistic perspective. In this approach, the membrane protein target is transiently solubilized with a detergent in the presence of phospholipids and an encircling amphipathic helical protein belt, termed a membrane scaffold protein (MSP). The membrane protein then finds itself in a native membrane environment and is rendered soluble via the encircling MSP belt. The lab remains committed to the widest possible dissemination of the Nanodisc technology, including materials, methods and latest data from our laboratory. The Nanodisc system is now being used by hundreds of laboratories around the world that have realized great success and further advanced the technology. The American Society for Biochemistry and Molecular Biology (ASBMB) is a nonprofit scientific and educational organization with over 12,000 members. Founded in 1906, The Society's purpose is to advance the science of biochemistry and molecular biology through publication of scientific and educational journals. Dr Sligar’s Lectureship award is given bi-annually and provides a plaque, honorarium and costs related to presenting a named lecture at the ASBMB Annual Meeting, which will be held in April. Dr. Sligar is the inventor of Nanodisc technology and currently holds the University of Illinois Swanlund Endowed Chair, the highest endowed position at the University. He is also the Director of the School of Molecular and Cellular Biology and is a professor of biochemistry, chemistry, and biophysics and computational biology and an affiliate of the Institute for Genomic Biology and the Micro and Nano Technology Laboratory. To learn more about the usage of the Nanodisc nanotechnology, visit www.BioNanoCon.com or Sligar Lab.
Posted August 09, 2015
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Dr. Supriya Prasanth's lab identifies a BEN domain-containing protein as a novel transcriptional repressor of rRNA genes, in PNAS.
Rate of ribosome biogenesis dictates protein translational capacity of cells. Ribosomal RNA (rRNA), transcribed from tandem repeat units (rDNA), forms the major component of the ribosome. Therefore, transcriptional output from rDNA directly correlates with cell growth and proliferation and is often upregulated in several cancers.
Several mechanisms ensure controlled transcriptional output from rRNA genes. Transcriptional repression of a subset of rRNA genes is essential to maintain equilibrium in ribosome abundance. The study spearheaded by Dr. Abid Khan, a postdoctoral associate from Supriya Prasanth’s laboratory, identified a BEN domain-containing protein, BEND3, as a novel transcriptional repressor of rRNA genes.
Prasanth and colleagues show that BEND3 directly binds to rDNA promoter in a sequence specific manner and induces chromatin modifications leading to a transcriptionally repressive chromatin environment. BEND3 associates with the nucleolar-remodeling complex (NoRC), a major complex known to establish and maintain rDNA heterochromatin. SUMOylated BEND3 stabilizes Tip5, the bona fide component of NoRC via association with USP21 deubiquitinase. This study provides mechanistic insights into the regulation of NoRC stability and its implication in rDNA transcriptional repression. This work is published in PNAS (USA).
"What Matters" - 2015 Commencement address delivered by alumna, Dr. Tamara Helfer
Dr. Tamara Helfer, center, with Brad Mehrtens, Tina Knox, Stephen Sligar, and one of Dr. Helfer’s special deliveries on the left, the mini Mehrtens.
Dr. Tamara Helfer practices Obstetrics and Gynecology with Christie Clinic in Champaign, IL. A graduate of the University of Illinois, Dr. Helfer earned her BS in Microbiology and MBA from the University of Illinois at Urbana-Champaign. She earned her medical degree at the University of Illinois College of Medicine in Peoria, IL and completed her residency at the University of Missouri Hospital in Columbia, MO.
Dr. Helfer reminded graduates that “what matters” are the people and the process, not necessarily the outcome. And though graduates will soon get caught up in the frenzy of work life or further studies, Dr. Helfer reminded all to listen, be present, embrace failure, and be passionate. Her advice for new professionals: be humble; believe in people and trust; stay true to yourself; and say yes to life, love, and opportunity.
Dr. Helfer has served on multiple committees for The American Congress of Obstetricians and Gynecologist, ACOG, including the Coding and Health Economics, the Practice Management and the Industrial Exhibits Committee. She has been ACOG’s District VI Young Physician for the past 7 years, and is the Past President of the Champaign County Medical Society. Dr. Helfer enjoys having undergraduates, midlevel care providers, and medical students from the University of Illinois shadow her Practice. Once a semester, she is a guest lecturer to undergraduates and speaks on Ethics in Medicine.
Posted June 30, 2015
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Kevin Yum’s outstanding undergraduate career
His undergraduate research focused on understanding the pathogenesis of Myotonic Dystrophy type 1 (DM1), an autosomal dominant neuromuscular disease that affects 1 in 8,000 individuals worldwide. As an undergraduate researcher, Kevin investigated the role of muscleblind-like splicing factor 1 (MBNL1) and its implications in DM1 liver pathology and misregulation of alternative splicing.
“I enjoyed working with Dr. Kalsotra on the DM1 project, since it is a rare disease caused by toxic RNA gain-of-function that sequesters an essential splicing factor MBNL1. Fully elucidating the mechanism of this disease will not only lead us to devise new therapeutic approaches to treat DM1 patients but also discover other RNA-mediated disease-causing mechanisms and revolutionize the way we think about current diseases.” said Kevin.
Kevin also commented that his research experience at Illinois was truly amazing. He not only learned about the most cutting edge techniques in biochemistry and molecular biology but was able to apply many of those techniques in actual research.
“Since there are such diverse research areas covered by the distinguished MCB/Biochemistry faculty members on our campus, it was easy for me to find the lab that sparked my interest and advanced my understanding of basic science,” he said. “I was able to benefit from attending weekly seminars hosted by the school of MCB, where both graduate and undergraduate students can participate to explore current topics and latest research in the field.”
In addition to receiving the departmental awards, Kevin also won the Outstanding Oral Presentation Award during the campus-wide Undergraduate Research Week as well as the James Scholar Preble Research Scholarship. He believes that these accomplishments could not have been made without the invaluable skills in grant writing and research presentation he obtained from taking senior seminar courses.
Kevin plans to continue working in the Kalsotra lab for the next two years before pursuing a combined MD/PhD degree. His long-term goal is to seek a career in academia in order to teach and motivate the next-generation of students to become scientists.
Posted June 26, 2015
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Biochemistry graduate student wins NSF pre-doctoral fellowship
Livezey is currently working on two projects with Professor Shapiro, whose focus is on the discovery and use of novel small molecule biomodulators to identify and analyze interactions and pathways important in cancer and in the development of these small molecules as potential anticancer drugs.
Livezey’s first project is working on getting a new anti-cancer drug, BHPI, ready for clinical trials by figuring out how exactly the drug is so successful at shrinking tumors.
Her second project explores the pathway by which estrogen is protective in neurodegenerative diseases, such as Parkinson’s and Alzheimer’s.
Livezey says that her interest in these projects and the Shapiro Lab is not just because the science is so fascinating but also because the experience of disease in her own family has motivated her to search for cures. “I understand what the possible impacts are, and that is why science is so great.”
A first-year graduate student, Livezey chose the University of Illinois’s Biochemistry department because of the variety of biochemical research being done, including structural biology using crystallography; the physiology-related work; and the connection with the Chemical Biology department.
She applied for the fellowship during her second rotation with Biochemistry Affiliate Dr. Jefferson Chan, who, along with Dr. Auinash Kalsotra (Assistant Professor in Biochemistry), Livezey credits for providing significant feedback on her research statement and application.
The NSF Graduate Research Fellowship Program (GRFP) is awarded yearly to ensure the vitality and diversity of the scientific and engineering workforce of the United States. The program recognizes and supports outstanding graduate students who are pursuing research-based master's and doctoral degrees in science and engineering. The GRFP provides three years of support for the graduate education of individuals who have demonstrated their potential for significant achievements in science and engineering.
Posted May 06, 2015
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A new RNA repair complex employing a “one-stop shopping” repair mechanism
To fight for a limited resource of nutrition in the wildness, microbes release toxins to kill their neighbors to increase their share of nutrition. A majority of toxins are ribotoxins that cleave essential RNAs involved in protein translation, which are conserved in and required for all organisms to live. To counter the damage inflicted by ribotoxins, organisms employ protein enzymes to repair the damaged RNA for survival. Over the past several years, the Huang group has been engaged in discovery, biochemical and structural characterization of RNA repair systems. Significant research includes the discovery of a Pnkp–Hen1 RNA repair complex that carries out RNA repair with immunity. In the present study, published in the journal Nature Communications, Huang and coworkers described the discovery and characterization of a new bacterial RNA repair complex. The approach involved bioinformatic analyses to reveal the presence of a new putative RNA repair system in certain bacteria. The genes encoding three proteins (named Pnkp1, Rnl, and Hen1) that constitute the putative new RNA repair system were then cloned into expression vectors. All three proteins were overexpressed in E. coli and purified to homogeneity. In vitro reconstitution using the purified recombinant proteins and a ribotoxin-cleaved RNA substrate demonstrated that RNA repair requires the presence of all three proteins. Furthermore, the three proteins were shown to form a heterohexamer in vitro. Huang and coworkers were able to crystallize and solve the structure of the Pnkp–Rnl–Hen1 heterohexamer. The structure revealed the molecular architecture of the heterohexamer as two ring structures of Pnkp1–Rnl–Hen1 heterotrimer fused at the Pnkp1 dimer interface. The four active sites required for RNA repair are located on the inner rim of each ring, reminiscent of architectures of shopping malls. This particular arrangement of the four active sites suggests that RNA repair might be carried out via a “one-stop shopping” mechanism. Unlike the Pnkp–Hen1 RNA repair complex, which is present in many bacteria, the newly discovered Pnkp1–Rnl–Hen1 RNA repair complex is only found in ten bacterial species so far. Interestingly, the majority of the bacteria possessing the newly discovered RNA repair complex live in gingival plaques of human mouth. Huang hypothesized that the unique RNA repair carried out by the Pnkp1–Rnl–Hen1 complex in these bacteria might provide them with a heightened ability to survive. If this hypothesis proves to be correct, inhibiting RNA repair might provide a vehicle to reduce the population of these bacteria, which are linked to human dental and gum diseases. Development of small-molecule inhibitors of the new RNA repair complex is currently underway in Huang laboratory to test this possibility.
Microbes Scared to Death by Virus Presence
University of Illinois researchers found that Sulfolobus islandicus can go dormant, ceasing to grow and reproduce, in order to protect themselves from infection by Sulfolobus spindle-shaped virus 9 (SSV9). The dormant microbes are able to recover if the virus goes away within 24 to 48 hours—otherwise they die. “The microbe is hedging its bet,” said Associate Professor of Microbiology Rachel Whitaker, who led the research at the Carl R. Woese Institute for Genomic Biology. “If they go dormant, they might die, but we think this must be better than getting infected and passing it on.” Sulfolobus is a species of archaea (a domain of single-celled organisms distinct from bacteria) found in acidic hot springs all over the world, where free viruses are not as common as in other environments. These microbes will go dormant in the presence of just a few viruses, whether active or inactive. While inactivated virus particles cannot infect a host, Whitaker’s lab found they could still cause dormancy, and ultimately, death in Sulfolobus. “People thought these inactivated viruses were just an accident, that they were just mispackaged,” Whitaker said. “Now we know they are being sensed by the host so they are having an effect. People are starting to think that it is adaptive for the virus to produce inactivated virus particles.” Sulfolobus have an adaptive immune system found in archaea and bacteria that allows the microbe to encode a specific piece of DNA that matches the viral DNA, causing it to target the viral DNA and degrade it thus preventing the virus from propagating, or reproducing. Cultures with immunity to SSV9 recover from dormancy and grow normally once the virus is removed from the culture. Microbes without this immunity are susceptible to infection and eventually kill their neighbors by maintaining viral particles in the environment. The researchers do not know exactly what is going on while the microbes are dormant, only that the microbes look drastically different in that state. More research is needed to better understand these new interactions between microbes and viruses. Incorporating these findings into models will show the true ecological impact of viruses in the microbial world, Whitaker said. “We really don’t understand the way that viruses affect microbes,” Whitaker said. “There is a lot to learn. These communities are usually modeled where a virus will either kill the microbe or the microbe is resistant. But actually there are all these other subtleties going on, like dormancy, that are having a bigger impact than we understand.” Dormant microbes are found everywhere, in water, soil, and even the human gut, said Maria Bautista, a graduate student in Whitaker’s lab, who led the research. “Many microbes go dormant when they face environmental stress such as a change in pH or temperature ” Bautista said. “Maybe virus-induced dormancy is something that doesn’t just happen in Sulfolobus; it may be a widespread response to viruses in other environments. We don’t know.” The NSF supported this work. The paper, “Virus-Induced Dormancy in Archaeon Sulfolobus islandicus,” is available online (doi:10.1128/mBio.02565-14). Article by Claire Sturgeon and photo by Kathryn Coulter, Carl R. Woese Institute for Genomic Biology
New drug stalls estrogen receptor-positive cancer cells and shrinks tumors
An experimental drug rapidly shrinks most tumors in a mouse model of human breast cancer, researchers report in the Proceedings of the National Academy of Sciences. When mice were treated with the experimental drug, BHPI, “the tumors immediately stopped growing and began shrinking rapidly,” said University of Illinois biochemistry professor and senior author David Shapiro. “In just 10 days, 48 out of the 52 tumors stopped growing, and most shrank 30 to 50 percent.” The key to the drug’s potency lies in its unusual mode of action, Shapiro said. “BHPI works through the estrogen receptor protein, but in a way that is different than estrogenic hormones,” he said. “The drug hyperactivates a pathway called the unfolded protein response, which estrogens normally use to protect cells from stress and help them grow.” Rather than blocking the stress response, BHPI kicks the UPR into overdrive, said M.D./Ph.D. student and lead author Neal Andruska. “This drives the cancer cells from using the UPR in a protective way into making it a lethal pathway,” Andruska said. “In this way, it stops growth and eventually kills many types of breast, ovarian and endometrial cancer cells that contain estrogen receptor.” BHPI shuts down the production of new proteins, including proteins that normally keep the stress response pathway in check, Andruska said. “Eventually, many cancer cells die – in part because they can’t make any new proteins,” he said. BHPI spurs a number of events in the cell, including the opening of calcium channels in the endoplasmic reticulum, a special intracellular compartment. The influx of calcium into the cytoplasm sets off a cascade of events that prepare the cell to deal with stress. The cells try to pump the calcium back into its compartment, but BHPI keeps the calcium channels open, allowing the calcium to flow back into the cytoplasm. After about 30 minutes of this “futile cycle,” the cells run low on energy. (Watch a movie of cancer cells responding to estrogen and BHPI: Anticancer Drug BHPI Hyperactivates a Cell Stress Response to Kill Cancer Cells) “Without enough energy, cancer cells don’t grow,” Shapiro said. The cascade initiated by BHPI eventually turns on four pathways, “each of which could potentially contribute to the death of the cancer cells,” he said. Because the UPR pathway is overexpressed in therapy-resistant cancer cells, the drug is especially effective in targeting estrogen receptor-positive cells that are resistant to tamoxifen and other anti-cancer drugs, the researchers report. “BHPI works equally well in the presence or absence of estrogen,” Shapiro said. The mice that received the drug tolerated it well, with no weight loss or other negative side effects, the researchers said. “It’s still in the early days for this drug, and there are many hurdles to overcome to bring BHPI to the clinic,” Shapiro said. “But so far, it’s been clearing the hurdles by a wide margin.” The study team also includes researchers from the U. of I. department of food science and human nutrition, the department of molecular and integrative physiology, the College of Medicine and the U. of I. Cancer Center. The National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health and the Department of Defense Breast Cancer Research Program funded this research. Article by Diana Yates, News Bureau Photo by L. Brian Stauffer, News Bureau
Read coverage of the research in the News-Gazette.
Read the full PNAS article here.
Posted April 06, 2015
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A new hat for Aip1: Uncovering new roles for Aip1 in the disassembly of filamentous actin
Disassembly of actin filaments is important for many processes that involve rapid reorganization of cell shape such as cell movement and division. Cofilin is a vital disassembly protein however one limitation of cofilin is that it can stabilize filaments at saturating concentrations. Nadkarni and Brieher showed that the amount of cofilin in thymus extract is too high to allow disassembly of single actin filaments in solution. They discovered that Aip1 is able to disassemble filaments even in the presence of stabilizing concentrations of cofilin. In the presence of Aip1, stable filaments underwent increased severing and disassembly at filament ends. This indicated that Aip1 could act all along the sides of cofilin-decorated actin filaments. However, previous work had shown that Aip1 was a capping factor that acted at filament ends. Nadkarni and Brieher went on to show that Aip1 acts differently than a well-characterized capping factor CapZ, and does not behave like a capping factor. This led to a revision of the view of Aip1's mode of action on actin filaments.
Professor Phillip Newmark elected Fellow of the American Association for the Advancement of Science (AAAS).
Newmark was cited for his work in developmental biology, with particular emphasis on regeneration and germ cell development in flatworms, which carry profound implications for the field of regenerative medicine by their ability to regenerate from just a small sample of tissue. Newmark studies how their stem cells contribute to regeneration and tissue maintenance. He earned his PhD from the University of Colorado at Boulder in 1994 and joined the U of I faculty in 2001. Newmark is also an investigator of the Howard Hughes Medical Institute, and the recipient of a CAREER Award from National Science Foundation, and a Damon Runyon Scholar Award from the Damon Runyon Cancer Research Foundation. He has been named a University Scholar. The AAAS, the world’s largest general scientific society, was founded in 1848. Fellows have been elected to the organization since 1874. The organization’s stated goal is to “advance science, engineering, and innovation throughout the world for the benefit of all people.”
Posted December 18, 2014
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Jongsook Kim Kemper’s lab discovers that elevated acetylation of FXR in obesity promotes hepatic inflammation, published in the EMBO Journal
Posttranslational acetylation of transcriptional regulators is often persistently elevated in nutrient-excessive obesity conditions. In this study, we investigated the functional consequences of such elevated acetylation of the key metabolic regulator and bile acid nuclear receptor FXR. Proteomic studies identified Lys-217 as the FXR acetylation site in diet-induced obese mice. In vivo studies utilizing acetylation-mimic and acetylation-defective Lys-217 mutants and gene expression profiling revealed that FXR acetylation increased proinflammatory gene expression, inflammatory responses, and liver fat levels, and impaired insulin sensitivity. Mechanistically, agonist-activated FXR is SUMO2-modified at lysine 277 by the PIASy SUMO E3 ligase. SUMOylation of FXR inhibits inflammatory gene expression in response to inflammatory signaling. Selective transrepression of inflammatory genes results from increased interaction of SUMO-FXR with NF-kB. In obese mice, FXR acetylation at lysine 217 inhibits its SUMOylation and diminishes SUMO2-dependent FXR anti-inflammatory action. There are several important aspects to this study. First, although posttranslational modifications (PTMs) of proteins have been extensively studied, there is little evidence establishing the physiological/pathological relevance of PTMs and the mechanisms underlying PTM-mediated selective gene regulation. The present study, for the first time, demonstrates the relevance in vivo of a functional antagonism between acetylation and SUMOylation of FXR in diet-induced obese mice. Second, agonist-activated SUMOylated FXR selectively trans-represses NF-κB target inflammatory genes without transcriptionally regulating conventional FXR/RXRα target genes and further, the results indicate that the underlying mechanism is the selective interaction of SUMO2-FXR with NF-κB and not with RXRα. Third, since FXR is expressed in many non-hepatic tissues, including intestine, kidney, endothelial cells, and macrophages, the dysregulated acetyl/SUMO switch identified for liver FXR in obesity may also play a role in the pathogenesis of inflammatory diseases in other tissues, such as inflammatory bowel disease and atherosclerosis, as well as, liver steatohepatitis. Targeting the dysregulated acetyl/SUMO switch of FXR may provide novel therapeutic options and diagnostic markers for obesity-related inflammatory and metabolic disorders. This study was supported by grants from National Institutes of Health to Professor Kemper and a post-doctoral fellowship from America Heart Association to Dong-Hyun Kim.