Proteins are encoded by stored inherited genetic information and perform most of the catalytic and structural functions in living cells. Protein biosynthetic quality control orchestrates the elimination of newly synthesized proteins unable to achieve conformational maturation. It is of great medical importance because efficient clearance of aberrant proteins, and the lack thereof, contribute to the molecular pathogenesis associated with multiple loss-of-function and gain-of-toxic function disorders, respectively. Arguably, the system is best understood for secretory and membrane proteins that traverse compartments of the exocytic pathway prior to final deployment. Asparagine-linked oligosaccharides function as an appendage through which a small ensemble of glycan processing and recognition elements orchestrate the degradation of aberrant glycoproteins in the early exocytic pathway as a post-translational checkpoint in eukaryote genome expression. Modification of the glycans by ER mannosidase I (ERManI), when bound to nonnative protein structure, generates the degradation signal. The concentration of ERManI controls the rate, and accuracy, of substrate selection by controlling the time at which asparagine-linked glycans are modified following glycoprotein synthesis. Neither the mechanism(s) by which the concentration is controlled, or the contribution of ERManI regulation in the etiology of disease have been investigated. We have begun to uncover the regulatory pathways, and preliminary data are consistent with a model in which an elevated ERManI concentration plays a protective role by delaying the onset of liver cirrhosis associated with the accumulation of aberrant alphal-antitrypsin PI Z polymers in the ER of liver hepatocytes. Moreover, low ERManI levels coincide with development of the early-onset cirrhotic phenotype. The immediate goals are to dissect two novel regulatory pathways for ERManI, and delineate their participation in the etiology of the early- and late-onset gain-of-toxic-function disorders.
The specific aims are to: (1) dissect the signals that mediate post-translational down-regulation of human ERManI, (2) characterize the link between ERManI regulation and the unfo. The findings will demonstrate how glycoprotein biosynthetic quality control can function as a disease modifier, possible diagnostic marker, and potential site for therapeutic intervention. Moreover, the study will have broad implications, and serve as a paradigm, for the investigation of numerous protein-folding diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK064232-04S1
Application #
7863026
Study Section
Physiological Chemistry Study Section (PC)
Program Officer
Serrano, Jose
Project Start
2009-07-17
Project End
2011-06-30
Budget Start
2009-07-17
Budget End
2011-06-30
Support Year
4
Fiscal Year
2009
Total Cost
$48,997
Indirect Cost
Name
Baylor College of Medicine
Department
Pathology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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Sifers, Richard N (2013) Resurrecting the protein fold for disease intervention. Chem Biol 20:298-300
Pan, Shujuan; Cheng, Xiaoyun; Chen, Hongan et al. (2013) ERManI is a target of miR-125b and promotes transformation phenotypes in hepatocellular carcinoma (HCC). PLoS One 8:e72829
Pan, Shujuan; Cheng, Xiaoyun; Sifers, Richard N (2013) Golgi-situated endoplasmic reticulum ?-1, 2-mannosidase contributes to the retrieval of ERAD substrates through a direct interaction with ?-COP. Mol Biol Cell 24:1111-21
Pan, Shujuan; Wang, Shufang; Utama, Budi et al. (2011) Golgi localization of ERManI defines spatial separation of the mammalian glycoprotein quality control system. Mol Biol Cell 22:2810-22
Sifers, Richard N (2010) Intracellular processing of alpha1-antitrypsin. Proc Am Thorac Soc 7:376-80
Termine, Daniel J; Moremen, Kelley W; Sifers, Richard N (2009) The mammalian UPR boosts glycoprotein ERAD by suppressing the proteolytic downregulation of ER mannosidase I. J Cell Sci 122:976-84
Pan, Shujuan; Huang, Lu; McPherson, John et al. (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 50:275-81
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Wu, Ying; Termine, Daniel J; Swulius, Matthew T et al. (2007) Human endoplasmic reticulum mannosidase I is subject to regulated proteolysis. J Biol Chem 282:4841-9

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