Richard N Sifers, Ph.D.
Richard N Sifers, Ph.D.
Pathology and Immunology
Baylor College of Medicine
Houston, TX US
- Director of Operations and Membership
Center for Drug Discovery
Dan L Duncan Comprehensive Cancer Center
Baylor College of Medicine
Houston, Texas United States
- Ph.D. from University Of Oklahoma College Of Medicine
- 01/1984 - Oklahoma City, OK United States
- B.S. from Missouri Western State University
- 01/1978 - St. Joseph, MO United States
- Secretory Pathway
- Protein Biosynthetic Quality Control
- Conformational Disease
- Alpha1-antitrypsin Deficiency
- Disease Modifiers
- ER Stress and Unfolded Protein Response
- Cell Stress Responses and Cancer Cell Pro-Survival
Professional StatementGenetic 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.
- Liu Y, Choudhury P, Cabral CM, Sifers RN "Oligosaccharide modification in the early secretory pathway directs the selection of a misfolded glycoprotein for degradation by the proteasome.." J. Biol. Chem.. 1999 Feb 26;274(9):5861-7. Pubmed PMID: 10026209
- Cabral CM, Choudhury P, Liu Y, Sifers RN "Processing by endoplasmic reticulum mannosidases partitions a secretion-impaired glycoprotein into distinct disposal pathways.." J. Biol. Chem.. 2000 Aug 11;275(32):25015-22. Pubmed PMID: 10827201
- Cabral CM, Liu Y, Sifers RN "Dissecting glycoprotein quality control in the secretory pathway.." Trends Biochem. Sci.. 2001 Oct;26(10):619-24. Pubmed PMID: 11590015
- Cabral CM, Liu Y, Moremen KW, Sifers RN "Organizational diversity among distinct glycoprotein endoplasmic reticulum-associated degradation programs.." Mol. Biol. Cell. 2002 Aug;13(8):2639-50. Pubmed PMID: 12181335
- Sifers RN "Protein degradation unlocked.." Science. 2003 Feb 28;299:1330-1331. Pubmed PMID: 12610289
- Wu Y, Swulius MT, Moremen KW, Sifers RN "Elucidation of the molecular logic by which misfolded alpha 1-antitrypsin is preferentially selected for degradation.." Proc. Natl. Acad. Sci. U.S.A.. 2003 Jul 8;100(14):8229-34. Pubmed PMID: 12815101
- Sifers RN "Insights into checkpoint capacity.." Nat. Struct. Mol. Biol.. 2004 Feb;11(2):108-9. Pubmed PMID: 14749767
- Termine D, Wu Y, Liu Y, Sifers RN "Alpha1-antitrypsin as model to assess glycan function in endoplasmic reticulum.." Methods. 2005 Apr;35(4):348-53. Pubmed PMID: 15804606
- Mast SW, Diekman K, Karaveg K, Davis A, Sifers RN, Moremen KW "Human EDEM2, a novel homolog of family 47 glycosidases, is involved in ER-associated degradation of glycoproteins.." Glycobiology. 2005 Apr;15(4):421-36. Pubmed PMID: 15537790
- Wu Y, Termine DJ, Swulius MT, Moremen KW, Sifers RN "Human endoplasmic reticulum mannosidase I is subject to regulated proteolysis.." J. Biol. Chem.. 2007 Feb 16;282(7):4841-9. Pubmed PMID: 17166854
- Mallya M, Phillips RL, Saldanha SA, Gooptu B, Brown SC, Termine DJ, Shirvani AM, Wu Y, Sifers RN, Abagyan R, Lomas DA "Small molecules block the polymerization of Z alpha1-antitrypsin and increase the clearance of intracellular aggregates.." J. Med. Chem.. 2007 Nov 1;50(22):5357-63. Pubmed PMID: 17918823
- Pan S, Wang R, Zhou X, Corvera J, Kloc M, Sifers R, Gallick GE, Lin SH, Kuang J "Extracellular Alix regulates integrin-mediated cell adhesions and extracellular matrix assembly.." EMBO J.. 2008 Aug 6;27(15):2077-90. Pubmed PMID: 18636094
- Termine DJ, Moremen KW, Sifers RN "The mammalian UPR boosts glycoprotein ERAD by suppressing the proteolytic downregulation of ER mannosidase I.." J. Cell. Sci.. 2009 Apr 1;122:976-84. Pubmed PMID: 19258393
- Pan S, Huang L, McPherson J, Muzny D, Rouhani F, Brantly M, Gibbs R, Sifers RN "Single nucleotide polymorphism-mediated translational suppression of endoplasmic reticulum mannosidase I modifies the onset of end-stage liver disease in alpha1-antitrypsin deficiency.." Hepatology. 2009 Jul;50(1):275-81. Pubmed PMID: 19444872
- Sifers RN "Manipulating proteostasis.." Nat. Chem. Biol.. 2010 Jun;6(6):400-1. Pubmed PMID: 20479748
- Sifers RN "Intracellular processing of alpha1-antitrypsin.." Proc Am Thorac Soc. 2010 Nov;7(6):376-80. Pubmed PMID: 21030516
- Pan S, Iannotti MJ, Sifers RN "Analysis of serpin secretion, misfolding, and surveillance in the endoplasmic reticulum.." Meth. Enzymol.. 2011;499:41290. Pubmed PMID: 21683246
- Pan S, Wang S, Utama B, Huang L, Blok N, Estes MK, Moremen KW, Sifers RN "Golgi localization of ERManI defines spatial separation of the mammalian glycoprotein quality control system.." Mol. Biol. Cell. 2011 Aug;22(16):2810-22. Pubmed PMID: 21697506
- Pan S, Cheng X, Sifers RN "Golgi-situated endoplasmic reticulum a-1, 2-mannosidase contributes to the retrieval of ERAD substrates through a direct interaction with ?-COP.." Mol. Biol. Cell. 2013 Apr;24(8):1111-21. Pubmed PMID: 23427261
- Pan S, Cheng X, Chen H, Castro PD, Ittmann MM, Hutson AW, Zapata SK, Sifers RN. "ERManI Is a Target of miR-125b and Promotes Transformation Phenotypes in Hepatocellular Carcinoma (HCC).." PLoS One. 2013 Aug 5;8(8) Pubmed PMID: 23940818
- Iannotti MJ, Figard L, Sokac AM, Sifers RN. "A Golgi-localized mannosidase (MAN1B1) plays a non-enzymatic gatekeeper role in protein biosynthetic quality control.." J Biol Chem.. 2014 Apr 25;289(17):11844-11858. Pubmed PMID: 24627495
- Mamrosh JL, Lee JM, Wagner M, Stambrook PJ, Whitby RJ, Sifers RN, Wu SP, Tsai MJ, Demayo FJ, Moore DD. "Nuclear receptor LRH-1/NR5A2 is required and targetable for liver endoplasmic reticulum stress resolution.." Elife. 2014 Apr 15; Pubmed PMID: 24737860
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