Richard N. Sifers, Ph.D.
Associate Professor
Departments of Pathology, Molecular & Cellular Biology,
Cell and Molecular Biology Interdepartmental Graduate
Program
Baylor College Medicine, Building: Ben Taub Research
Center
Room: BCMT-T240
Phone: 713.798.3169
E~mail: rsifers@bcm.tmc.edu
RESEARCH INTERESTS: Cellular Glycobiology and Conformational Disease
Protein biosynthetic quality control systems eliminate aberrant gene products from the living cell to extend a cohesive series of checkpoints beyond the nucleus to monitor the fidelity of gene expression. Presently, the individual components and molecular logic that underlie quality control are best understood for proteins transported though the secretory pathway which, along with the nuclear envelop, led to the evolution of eukaryotes. 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. 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), when bound to nonnative structure, generates a "degradation signal" that broadcasts impaired folding efficiency. Recognition of the signal by EDEM (ER degradation-enhancing mannosidase-like protein) precedes recruitment of the substrate to proteolytic machinery. Our findings indicate that the steps of substrate selection, tagging, and recruitment are highly regulated. Also, distinct folding and degradation programs can operate in a cell-specific manner and diverge in the manner by which the degradation signal is recognized, as well as the proteolytic machinery available for degradation. Since 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.), ER 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.
Selected Publications
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.