Richard N. Sifers, Ph.D.Professor of Pathology, Molecular & Cellular Biology, and Molecular Physiology & Biophysics
Description of Work
- Genetic information is inherited as DNA and stored in the nucleus. Despite this important role, the encoded proteins are responsible for performing most of the catalytic and structural functions that take place in living cells. Importantly, protein folding and quality control systems comprise two branches of a post-translational gene expression checkpoint. Their contribution to disease pathogenesis is illustrated by their conspicuous involvement in numerous loss-of-function and gain-of-toxic function disorders.
- Arguably, protein biosynthetic quality control is best understood in the secretory pathway where the processing of asparagine-linked oligosaccharides functions to orchestrate the elimination of numerous aberrant glycoproteins unable to acquire structural maturation. In particular, we have discovered that modification of the asparagine-linked appendage by endoplasmic reticulum mannosidase I (ERManI), in combination with non-native protein structure, is responsible for generating the degradation signal. Importantly, the concentration of ERManI controls the rate of substrate degradation by controlling the rate at which the degradation signal is formed.
- However, neither the mechanism by which the ERManI concentration is controlled or its contribution to disease pathogenesis is fully understood. We have begun to dissect this key regulatory pathway and have shown that the ERManI concentration is controlled at both translational and post-translational levels. Furthermore, preliminary data imply that an elevated ERManI concentration plays a protective role against the development of liver disease associated with plasma alpha1-antitrypsin deficiency, presumably by hindering the accumulation of PI Z polymers in the ER of liver hepatocytes. Likewise, an apparent failure to up-regulate the ERManI concentration coincides with the development of the early-onset form of the disorder.
- The immediate goals are to further dissect the mechanism of human ERManI regulation and delineate its participation in the etiology of the liver disease. The long term goal is to demonstrate how a core element of the glycoprotein quality control machinery can function as a disease modifier, possible diagnostic marker, and potential site for therapeutic intervention.
- Ph.D. University of Oklahoma, Health Sciences Center, Oklahoma City, OK
- B.S. Missouri Western State University, St. Joseph, MO
- Department of Cell Biology, Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX
- Cell Biology
Area of Interest
- Secretory pathway
- Protein biosynthetic quality control
- Conformational disease
- Alpha1-antitrypsin deficiency
- Disease modifiers
- ER stress and unfolded protein response
- Department of Pathology
- Department of Molecular and Cellular Biology
- Department of Molecular Physiology and Biophysics
- Program in Cellular and Molecular Biology
- Medical Scientist Training Program
- Program in Translational Biology and Molecular Medicine
- Program in Structural and Computational Biology and Biophysics
- Digestive Disease Center
- Dan L. Duncan Cancer Center
- Center for Liver Diseases
- Human Genome Sequencing Center
- Summer Medical and Research Training (SMART) Steering Committee
Professional Positions Held
- NIH, Hemostasis and Thrombosis (HT) Study Section
- NIH Intercellular Interactions (ICI) Study Section
- The Wellcome Trust
- The Alzheimer's Association, Alzheimer's Grant Review Program
- Peer Review Committee, American Heart Association
- The Alpha-1 Foundation
- Medical Research Council (MRC) of Britain ,
- Molecular and Cellular Medicine
- Medical Research Council of Canada
- Italian Telethon
- The Israel Science Foundation
- United States-Israel Bi-national Science Foundation
- Swiss National Science Foundation
- The Children's Research Center-Charitable Trust
- Our Lady's Hospital for Sick Children
- National Health and Medical Research Council of Australia
- National Science Foundation, Division of Mol. & Cell. Biosciences
- Editorial Board member, Alpha-1 Alliance Quarterly Journal
- Editorial Board member, World Journal of Biological Chemistry
Non-Profit organization membership:
- Alpha1-Foundation Medical and Scientific Advisory Committee
- Alpha 1-Foundation Educational Materials Working Group
- Alpha1-Foundation Liver Task Force
- "Organization of the Cell" graduate level course (co-Director and team teacher)
- "Structure of Macromolecules", graduate level course (team teacher)
- "Foundations of Basic Science to the Science of Medicine: Core Concepts"
Medical school course (team teacher)
- "Pathophysiology and Mechanisms of Human Disease", graduate level course (team teacher)
- Biology of Aging and Age-Related Disease" advanced graduate course
Honors and Awards
- Regents and Trustees Special Honor Scholarship, Missouri Western State University
- NIH Postdoctoral Fellowship Award, "Alpha1-antitrypsin Deficiency"
- American Lung Association Research Career Investigator Award
- Distinguished Guest Lecturer, Cincinnati Children's Research Foundation
- Distinguished Guest Lecturer, University of Miami Medical School
- "Best Course" Award, "Organization of the Cell"
- "Best Lecturer" Award
- Fulbright & Jaworski L. L. P. Faculty Excellence Award (Teaching and Evaluation)
- Academy of Distinguished Educators
- Invited Keynote Speaker, 3rd Protein Misfolding and Neurological Disorders
- Recipient of the Barbara and Corbin J. Robertson, Jr. Presidential Award for Excellence in Education
Professional Organization Memberships
- Basic Science Council
- American Heart Association
- American Society for Cell Biology
- American Society for Biochemistry and Molecular Biology
- American Society for Human Genetics
- New York Academy of Sciences
- American Chemical Society with IUPAC
- American Association for the Advancement of Science
- The Protein Society
- Society for Glycobiology
- Cell Stress Society International
- Liu Y, Choudhury P, Cabral CM and Sifers RN. (1999). Oligosaccharide modification in the early secretory pathway directs the selection of a misfolded glycoprotein for degradation by the proteasome. J. Biol. Chem. 274: 5861-5867.
- Cabral CM, Choudhury P, Liu Y and Sifers RN. (2000). Processing by endoplasmic reticulum mannosidases partitions a secretion-impaired glycoprotein into distinct disposal pathways. J. Biol. Chem. 275: 25015-25022.
- Cabral CM, Liu Y, and Sifers RN. (2001). Dissecting glycoprotein quality control in the secretory pathway. Trends Bioch. Sci. 26, 619-624.
- Cabral CM, Liu Y, Moremen KW and Sifers RN. (2002). Organizational diversity among distinct glycoprotein ER-associated degradation programs. Mol. Biol. Cell. 13:2639-2650.
- Sifers RN. (2003). Protein degradation unlocked. Science 299:1330-1331.
- Wu Y, Swulius MT, Moremen KW and Sifers RN. (2003). Elucidation of the molecular logic that preferentially targets misfolded alpha1-antitrypsin for intracellular degradation. Proc. Natl. Acad. Sci. USA 100, 8229-8234.
- Sifers, R.N. (2004). Insights into checkpoint capacity. Nature Struct. & Mol. Biol 11:108-109.
- Termine, D., Wu, Y., Liu, Y. and Sifers. R.N . (2005) Alpha1-antitrypsin as a model for glycan function in the endoplasmic reticulum. METHODS 35(4):348-353.
- Mast, S.W., Diekman, K., Davis , A.W., Karaveg, K., Sifers, R.N . and Moremen, K.W. (2005). Human EDEM2, a novel homolog of family 47 glycosidases, is involved in ER-associated degradation of glycoproteins. Glycobiology 15:421-436.
- Wu, Y., Termine, D.J., Swulius, M.T., Moremen, K.W., and Sifers, R.N. (2007). Human endoplasmic reticulum mannosidase I is subject to regulated proteolysis. J. Biol. Chem, 282;4841-4849.
- Mallya, M., Phillips, R.L., Saldanha, A., Gooptu, B., Brown, S.C.L, Shirvani, A., Termine, D.J., Wu, Y., Sifers, R.N., Abagyan, R., Lomas, D.A. (2007) Small molecules block the polymerisation of Z alpha-1-antitrypsin and increase the clearance of intracellular aggregates. J. Medicinal Chemistry 50;5357-5363.
- Pan, S., Wang, R., Zhou, X., Sun, L., Malforzata, M., Corvera, J., Sifers, R.N., Lin, S-H., Kuang, J. (2008) Extracellular Alix regulates integrin-mediated cell adhesions and extracellular matrix assembly. EMBO J 27(15):2077-2090.
- Termine, D.J., Moremen, K.W., and Sifers, R.N. (2009) The mammalian UPR boosts glycoprotein ERAD by suppressing the down-regulation of ER mannosidase I. Journal of Cell Science 122 (7): 964-976.
- Pan, S., Huang, L., McPherson, J., Muzny, D., Rouhani, F., Brantly, M., Gibbs, R., and Sifers. R.N . (2009) Single nucleotide polymorphism - mediated translational suppression of endoplasmic reticulum mannosidase I modifies the onset of end-stage liver disease in alpha1-antitrypsin deficiency. Hepatology 50 (1):275-281.