Stuart A. Kornfeld, M.D.

David C. & Betty Farrell Professor
Internal Medicine
Biochemistry and Molecular Biophysics

Molecular Cell Biology Program

  • 314-362-8803

  • 314-362-8828

  • 314-362-8826

  • 8125

  • 8826 Clinical Sciences Research Building


  • intracellular trafficking, receptor, mannose 6-phosphate, lysosome

  • Intracellular protein trafficking, including targeting of acid hydrolases to lysosomes

Research Abstract:

We study the biochemical and molecular basis for protein trafficking in mammalian cells, focusing on the biogenesis of lysosomes. The targeting of lysosomal enzymes from their site of synthesis in the rough endoplasmic reticulum to their final destination in lysosomes is a multistep process that utilizes a series of recognition signals that must be deciphered by cellular components that mediate the sorting, packaging and transport of the lysosomal enzymes. A key step in this pathway is the selective phosphorylation of mannose residues on the lysosomal enzymes. These residues allow binding to Man-6-P receptors in the Golgi and transport to lysosomes via clathrin-coated vesicles.

The goal of our work is to understand this complex sorting system at the molecular level. Our current focus is on the enzyme that mediates the first step in the generation of the Man-6-P recognition marker on the newly synthesized lysosomal acid hydrolases. N-acetylglucosamine-1-phosphotransferase is an α2β2γ2 hexamer encoded by two genes, GNPTAG and GNPTG. Mutations in these genes give rise to the lysosomal storage disorders Mucolipidosis II and III that are characterized by hypersecretion of acid hydrolases that lack the Man-6-P recognition marker. By studying the consequences of missense mutations in the GNPTAB and GNPTG genes found in patients with ML II and ML III, we are identifying the domains of the transferase that determine proper localization in the Golgi, the ability to recognize lysosomal acid hydrolases as specific substrates and the ability to mediate the catalytic function. We are also analyzing the consequences of mutations in these genes that have been discovered in individuals with persistent stuttering.

In related work the two genes that encode the subunits of N-acetylglucosamine-1-phosphotransferase have been disrupted in mice to generate models of ML II and ML III. These mutant mice are allowing us to analyze the development of tissue damage in these disorders.

Selected Publications:

1. Van Meel E, Qian Y, Kornfeld SA. Mislocalization of phosphotransferase as a cause of mucolipidosis III αβ. Proc Natl Acad Sci 2014 111:3532-3537.

2. Qian Y, Flanagan-Steet H, Van Meel E, Steet R, Kornfeld S. The DMAP interaction domain of UDP-GlcNAc:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase is a substrate recognition module. Proc Natl Acad Sci 2013 110:10246-10251.

3. Lee WS, Kang C, Drayna D, Kornfeld S. Analysis of Mannose 6-Phosphate Uncovering Enzyme Mutations Associated with Persistent Stuttering. J Biol Chem 2011 286:39786-39793.

4. Boonen M, Van Meel E, Oorschot V, Klumperman J, Kornfeld S. Vacuolization of mucolipidosis type II mouse exocrine gland cells represents accumulation of autolysosomes. Molec Biol Cell 2011 22:1135-1147.

5. Qian Y, Lee I, Lee W-S, Qian M, Kudo M, Canfield WM, Lobel P, Kornfeld S. Functions of the α, β and γ subunits of UDP-GlcNAc:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase. J Biol Chem 2010 285:3360-3370.

6. Lee WS, Payne BJ, Gelfman CM, Vogel P, Kornfeld S. Murine UDP-GlcNAc:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase lacking the γ-subunit retains substantial activity toward acid hydrolases. J Biol Chem 2007 282: 27198-27203.

7. Vogel P, Payne BJ, Read R, Lee W-S, Gelfman CM, Kornfeld S. Comparative Pathology of Murine Mucolipidosis Types II and IIIC. Veterinary Pathology 2008 46: 313-324.

Last Updated: 8/12/2014 3:31:36 PM

Back To Top

Follow us: