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Center for the Genetics of Host Defense

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Li X.,Hospital for Special Surgery | Maretzky T.,Hospital for Special Surgery | Perez-Aguilar J.M.,Biophysics and Systems Biology | Perez-Aguilar J.M.,IBM | And 7 more authors.
Journal of Cell Science | Year: 2017

A disintegrin and metalloproteinase 17 (ADAM17) controls the release of the pro-inflammatory cytokine tumor necrosis factor α (TNFα, also known as TNF) and is crucial for protecting the skin and intestinal barrier by proteolytic activation of epidermal growth factor receptor (EGFR) ligands. The seven-membrane-spanning protein called inactive rhomboid 2 (Rhbdf2; also known as iRhom2) is required for ADAM17-dependent TNFα shedding and crosstalk with the EGFR, and a point mutation (known as sinecure, sin) in the first transmembrane domain (TMD) of Rhbdf2 (Rhbdf2sin) blocks TNFα shedding, yet little is known about the underlying mechanism. Here, we used a structure-function analysis informed by structural modeling to evaluate the interaction between the TMD of ADAM17 and the first TMD of Rhbdf2, and the role of this interaction in Rhbdf2- ADAM17-dependent shedding. Moreover, we show that double mutant mice that are homozygous for Rhbdf2sin/sin and lack Rhbdf1 closely resemble Rhbdf1/2-/- double knockout mice, highlighting the severe functional impact of the Rhbdf2sin/sin mutation on ADAM17 during mouse development. Taken together, these findings provide new mechanistic and conceptual insights into the critical role of the TMDs of ADAM17 and Rhbdf2 in the regulation of the ADAM17 and EGFR, and ADAM17 and TNFα signaling pathways. © 2017. Published by The Company of Biologists Ltd.

News Article | June 20, 2017
Site: www.eurekalert.org

SAN DIEGO, June 20, 2017 -- Johnson & Johnson today named Douglas Wallace, Ph.D., of Children's Hospital of Philadelphia, winner of the 2017 Dr. Paul Janssen Award for Biomedical Research, and launched a campaign for champions of science as part of the Dr. Paul Janssen Project -- a new year-long, multi-faceted program to recognize the impact of science on humanity. The full breadth of the program will be announced at the Dr. Paul Janssen Award ceremony in September. Dr. Wallace won for his pioneering work in the field of mitochondrial genetics, and joins 14 other scientists who have received the Dr. Paul Janssen Award in the past 13 years, including two who went on to win the Nobel Prize. Mitochondrial DNA is genetic material found in mitochondria - tiny power plants within cells -- and is passed down exclusively from mothers. Dr. Wallace's groundbreaking work has led to a treasure trove of insights into our genealogy, and has implications for understanding and treating a range of metabolic and degenerative diseases, cancer and aging. "I am honored that such a distinguished committee has selected me to join the list of exceptional past winners of the Dr. Paul Janssen Award," said Dr. Wallace. "Of particular importance is that this Award focuses attention on the crucial role of mitochondrial DNA genetics and bioenergetics in the etiology of common metabolic and degenerative diseases. This perspective offers powerful new approaches for diagnosis and treatment of these ubiquitous maladies and thus for enhancing the health and well-being of all peoples." A video of Dr. Wallace's full acceptance comments can be viewed here. "We are proud to honor the legacy of Dr. Paul by celebrating today's pioneers like Dr. Wallace," said Paul Stoffels, M.D., Chief Scientific Officer, Johnson & Johnson. "We are expanding our Awards program to a year-round commitment to recognize the contributions of scientists all over the world to advancing human health." "Dr. Wallace's insatiable curiosity, tenacity, and passion for humanity exemplifies the spirit we hope to fuel by expanding our commitment to champion science through the Dr. Paul Janssen Project," said Seema Kumar, Vice President, Innovation, Global Health and Science Policy Communication, Johnson & Johnson. "This includes our longstanding support of programs like the Biotechnology Institute's BioGENEius Challenge, that inspire and encourage the next generation of innovators." To celebrate dedicated researchers like Dr. Wallace, and to fuel the next generation of passionate innovators globally, the company will donate $5, up to $50,000, to the Biotechnology Institute every time someone shows support for science by using #ChampionsofScience on social media channels through September 30, 2017i. Dr. Wallace is the founder and director of the Center for Mitochondrial and Epigenomic Medicine at Children's Hospital of Philadelphia, where he holds the Michael and Charles Barnett Chair of Pediatric Mitochondrial Medicine and Metabolic Disease. He also is a Professor of Pathology and Laboratory Medicine in the Perelman School of Medicine at the University of Pennsylvania. He is a member of the American Academy of Arts and Sciences, National Academy of Sciences, National Academy of Medicine, and the Accademia Nazionale delle Scienze detta dei XL (Italian National Academy of Science). "Dr. Wallace was the first to understand the power that mitochondrial genetics could bring to the study of human disease," said David Julius, Ph.D., Professor and Chair of the Department of Physiology, University of California, San Francisco, and Chair of the 2017 Dr. Paul Janssen Award selection committee. "It's great to recognize Dr. Wallace for his unique and groundbreaking research that has spanned nearly four decades." The winners of the Dr. Paul Janssen Award for Biomedical Research are chosen by an independent selection committee of the world's most renowned scientists. The Award, which includes a $200,000 prize, will be presented to Dr. Wallace during ceremonies in the U.S. and Belgium in September. About The Dr. Paul Janssen Award for Biomedical Research Dr. Paul Janssen was one of the 20th century's most gifted and passionate researchers. He helped save millions of lives through his contribution to the discovery and development of more than 80 medicines, four of which remain on the World Health Organization's list of essential medicines. The Dr. Paul Janssen Award for Biomedical Research was established by Johnson & Johnson in 2004 to honor the memory of Dr. Paul. Since its inception, the Award has recognized fifteen outstanding scientists, two of whom have gone on to win the Nobel Prize for the same work. Learn more about the Champions of Science movement and The Dr. Paul Janssen Award at http://www. . The Dr. Paul Janssen Award independent selection committee is composed of some of the world's leading scientists, including National Medal of Science winners, Nobel Laureates, members of the National Academy of Sciences and past winners of the Dr. Paul Janssen Award. David Julius, Ph.D. (chairman), Professor and Chair of the Department of Physiology at the University of California, San Francisco Bruce Beutler, M.D., Regental Professor, Director, Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center Jennifer Doudna, Ph.D., Professor of cell and molecular biology and of chemistry, University of California, Berkeley; Li Ka Shing Chancellor's Chair in Biomedical and Health Sciences; Investigator, Howard Hughes Medical Institute Dame Carol Robinson, DBE, FRS, FmedSci, Chair of Doctor Lee's Professor of Chemistry at the University of Oxford; Dame Commander of the Order of the British Empire Thomas Südhof, M.D., Avram Goldstein Professor in the School of Medicine and Professor of Molecular and Cellular Physiology at Stanford University Caring for the world, one person at a time, inspires and unites the people of Johnson & Johnson. We embrace research and science - bringing innovative ideas, products and services to advance the health and well-being of people. Our approximately 130,800 employees at more than 250 Johnson & Johnson operating companies work with partners in health care to touch the lives of over a billion people every day, throughout the world. For more information, visit http://www. . Between June 20, 2017 and September 30, 2017, Johnson & Johnson Services, Inc. will donate $5.00 to the Biotechnology Institute as part of the Champions of Science campaign for each eligible Facebook post, Tweet or other social media channel post using the "#ChampionsofScience" hashtag, with a minimum donation of $25,000 and a maximum donation of $50,000.

DALLAS - July 27, 2017 - Genes that regulate a cellular recycling system called autophagy are commonly mutated in Crohn's disease patients, though the link between biological housekeeping and inflammatory bowel disease remained a mystery. Now, researchers at UT Southwestern Medical Center have uncovered an intriguing clue. A research team led by Dr. Lora Hooper, Chair of Immunology at UT Southwestern and an Investigator of the Howard Hughes Medical Institute, has determined that a backup pathogen-fighting system uses autophagy's cellular machinery to deliver protein weapons to the front lines - the cell surface - in the fight against bacterial attack. "This is the first example of this alternative pathway being used in immune defense in any kind of animal," Dr. Hooper said of the mouse study, published online today in Science. The Centers for Disease Control and Prevention estimates that about 3 million U.S. residents suffer from inflammatory bowel disease with that number about equally split between Crohn's disease and ulcerative colitis. The two conditions are characterized by chronic inflammation of the gastrointestinal tract. Dr. Shai Bel, a postdoctoral researcher in Dr. Hooper's laboratory and the lead author of the study, said the significance of the study's findings rest on understanding the complex, dynamic ecosystem in the intestines. "Our guts are teeming with trillions of bacteria that do a great service by helping us digest food, but they can also cause illness if able to invade our tissues," Dr. Bel said. "To keep helpful bacteria at a safe distance, cells lining the intestine produce antimicrobial proteins - tiny weapons on the cell surface that target and kill bacteria that are threatening to invade intestinal cells." Dangerous pathogens, such as those that cause food poisoning, have developed advanced weapons systems aimed at overcoming that first line of defense, he continued. The secondary pathway seen in this study appears to send reinforcements to the battle lines on the cell surface, he added. Classical autophagy - for which Dr. Yoshinori Ohsumi of Japan was awarded the 2016 Nobel Prize in Physiology or Medicine - is a system cells use to degrade and recycle unneeded components. While the backup defense system observed in this study is not part of the classical autophagy pathway, it appears to use some of autophagy's cellular machinery. "This substitute pathway uses classical autophagy machinery to make and transport protein weapon reinforcements to the cell surface after the first line of defense fails," said Dr. Hooper, also a Professor of Immunology and Microbiology with an additional appointment in the Center for the Genetics of Host Defense. To study the backup defense system, the researchers used mice engineered by Boston collaborators to have the mutation seen in many human Crohn's patients and then exposed these mice to Salmonella, a foodborne pathogen. "When intestinal cells from normal, wild-type mice encounter Salmonella, their protein weapons travel through this detour, or backup pathway, and still make it to the battle lines on the cell surface," said Dr. Hooper, who holds the Jonathan W. Uhr, M.D. Distinguished Chair in Immunology and is a Nancy Cain and Jeffrey A. Marcus Scholar in Medical Research, in Honor of Dr. Bill S. Vowell. "In mice with this Crohn's mutation, the detour pathway is blocked and unable to kill bacteria. In agreement with these findings, our collaborators found that the mice got sicker when exposed to another foodborne pathogen." The researchers observed abnormalities in the intestinal lining of the mice that resembled abnormalities in protein packaging seen in the cells of Crohn's patients, she said. However, she stressed that Crohn's disease is a complicated condition, and this study did not involve any human testing. "Understanding of what is going on in Crohn's patients and the role of mutations in this backup defense system will take much more research," she said. "We believe this study provides a better understanding of what goes wrong in the intestinal lining in Crohn's patients. Time will tell." Dr. Sebastian Winter, Assistant Professor of Microbiology and a W.W. Caruth, Jr. Scholar in Biomedical Research; graduate students Mihir Pendse and Yuhao Wang; Dr. Yun Li, Instructor; Kelly Ruhn, a research technician; and research assistants Brian Hassell and Tess Leal, all of Immunology, also contributed to this work as did a researcher with joint appointments at the Broad Institute, Massachusetts General Hospital, and Harvard Medical School. The work received support from the National Institutes of Health, the Burroughs Wellcome Fund, the Welch Foundation, and the Howard Hughes Medical Institute. UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution's faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 18 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The faculty of more than 2,700 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 100,000 hospitalized patients, 600,000 emergency room cases, and oversee approximately 2.2 million outpatient visits a year. This news release is available on our website at http://www. To automatically receive news releases from UT Southwestern via email, subscribe at http://www.

PubMed | Center for the Genetics of Host Defense
Type: Review | Journal: Best practice & research. Clinical haematology | Year: 2016

As it is a hard-wired system for responses to microbes, innate immunity is particularly susceptible to classical genetic analysis. Mutations led the way to the discovery of many of the molecular elements of innate immune sensing and signaling pathways. In turn, the need for a faster way to find the molecular causes of mutation-induced phenotypes triggered a huge transformation in forward genetics. During the 1980s and 1990s, many heritable phenotypes were ascribed to mutations through positional cloning. In mice, this required three steps. First, a genetic mapping step was used to show that a given phenotype emanated from a circumscribed region of the genome. Second, a physical mapping step was undertaken, in which all of the region was cloned and its gene content determined. Finally, a concerted search for the mutation was performed. Such projects usually lasted for several years, but could produce breakthroughs in our understanding of biological processes. Publication of the annotated mouse genome sequence in 2002 made physical mapping unnecessary. More recently we devised a new technology for automated genetic mapping, which eliminated both genetic mapping and the search for mutations among candidate genes. The cause of phenotype can now be determined instantaneously. We have created more than 100,000 coding/splicing mutations. And by screening for defects of innate and adaptive immunity we have discovered many new proteins needed for innate immune function.

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