Richard N. Sifers, Ph.D.
Departments of Pathology, Molecular and Cellular Biology, and Molecular Physiology and Biophysics
Ph.D.: University of Oklahoma Health Sciences Center, Oklahoma City
Postdoctoral training: Baylor College of Medicine, Houston
Glycoprotein Folding, Quality Control, Oligosaccharides, Endoplasmic Reticulum, Conformational Disease, alpha1-Antitrypsin Deficiency, Glycobiology
Protein biosynthetic quality control systems eliminate aberrant gene products (proteins) from living cells to monitor the fidelity of gene expression. The individual components and molecular logic that underlie quality control are best understood for proteins transported though the secretory pathway. In the endoplasmic reticulum (ER), nascent secretory and cell surface proteins acquire native structure during physical engagement with molecular chaperones. Efficient conformational maturation is a rule that governs productive transport beyond the ER. Non-compliance results in the selective degradation of orphan subunits and misfolded polypeptides, usually by cytoplasmic proteasomes. The processing of asparagine-linked oligosaccharides represents the meeting point between glycoprotein folding and disposal processes. Modification of the asparagine-linked appendage by the slow-acting ER mannosidase I (ERManI) releases misfolded glycoproteins from the folding machinery, allowing for their degradation. The concentration of ERManI, which is highly regulated, plays a stochastic role is the “decision” that releases misfolded proteins from the folding machinery. Because the efficient, or inadequate, elimination of aberrant proteins underlies the molecular pathogenesis of numerous loss-of-function and gain-of-toxic-function disorders, respectively (e.g., cystic fibrosis, hypercholesterolemia, osteogenesis imperfecta, alpha1-antitrypsin deficiency, etc.), quality control warrants attention comparable to that given to other biological systems as a source for novel diagnostic markers and as a potential avenue for therapeutic intervention.
Most recently, the lab has begun to explore the capacity of single nucleotide polymorphisms in the gene for human ERManI to modify the severity of numerous inherited diseases caused by protein misfolding in the secretory pathway or excessive ER stress (i.e., diabetes). We are also using chemical biology in an attempt to prevent the misfolding of alpha1-antitrypsin and induce its secretion from cells.
- Fong J, Nguyen B, Bridger R, Medrano E, Wells L, Pan S and Sifers RN. (2012). Beta-N-acetylglucosamine (O-GlcNAc) is a novel regulator of mitosis-specific phophorylations on histone H3. J. Biol. Chem. 287:12195-12203.
- Pan S, Wang S, Utama B, Huang, Blok N, Estes MK, Moremen KW and Sifers RN. (2011). Golgi localization of ERManI defines spatial separation of the mammalian glycoprotein quality control system. Molecular Biology of the Cell 22(16) 2810-2822.
- Pan S, Huang L, McPherson J, Muzny D, Rouhani F, Brantly M, Gibbs R and Sifers RN. (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.
- Termine DJ, Moremen KW, and Sifers RN. (2009). The mammalian UPR boosts glycoprotein ERAD by suppressing the proteolytic down-regulation of ER mannosidase I. Journal of Cell Science 122(7):976-964.
- Mallya M, Phillips RL, Saldanha A, Gooptu B, Brown SCL, Shirvani A, Termine DJ, Wu Y, Sifers RN, Abagyan R, Lomas DA. (2007). Small molecules block the polymerisation of Z alpha-1-antitrypsin and increase the clearance of intracellular aggregates. J. Medicinal Chemistry 50(22):5357-5363.
- Wu Y, Termine DJ, Swulius MT, Moremen KW and Sifers RN. (2007). Human endoplasmic reticulum mannosidase I is subject to regulated proteolysis. J. Biol. Chem 282:4841-4849.
- Sifers RN. (2004). Insights into checkpoint capacity. Nature Struct & Mol Biol 11:108-109.
- Wu Y, Swulius MT, Moremen KW and Sifers RN. (2003). Elucidation of the molecular logic by which misfolded alpha1-antitrypsin is preferentially selected for intracellular degradation. Proc Natl Acad Sci (USA) 100:8229-8234.
- Sifers RN. (2003). Protein degradation unlocked. Science 299:1330-1331.
- 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.