My primary research is studying molecular mechanism of ion channel folding, assembly, degradation, trafficking, and function. I also focus on Ion channel folding diseases, such as genetic epilepsy, and proteostasis of membrane proteins.
Teaching Information
Office Hours
Research Information
Research Interests
Proteostasis maintenance of membrane proteins in health and disease
- We welcome graduate students to join the laboratory for rotations and thesis work.
My laboratory aims to understand protein homeostasis (proteostasis) of ion channels. They are major drug targets; loss of their proteostasis and thus function leads to numerous diseases, including neurological, neurodegenerative, and cardiovascular diseases. To function, ion channel proteins need to fold into their native structures and assemble properly in the endoplasmic reticulum (ER) for subsequent trafficking to the plasma membrane in a fully functional state. Mutations in a given protein could lead to protein misfolding and excessive ER-associated degradation (ERAD), and thus a significantly lowered concentration of proteins in cell membranes and loss of function.
Currently, in my laboratory, we focus on studying gamma-aminobutyric acid type A (GABAA) receptors. They are the primary inhibitory ion channels in the mammalian central nervous system. Loss of their function leads to epilepsies, autism, and other neurodevelopment diseases.
We explore how molecular chaperones, folding enzymes, ERAD factors, and trafficking factors, coordinate to facilitate membrane protein folding, assembly, degradation, and trafficking.
We also use small molecule proteostasis regulators to correct misfolded membrane proteins, as a therapeutic strategy to treat corresponding diseases.
Research Projects
1. Understanding the molecular mechanism underlying ion channel folding, assembly, and degradation
Because the activity of membrane proteins is coupled to other proteins in complicated cellular interaction networks, the molecular mechanism of ion channel folding and degradation in the cell has been elusive. Using representative membrane proteins, we aim to reveal the protein homeostasis network that controls their folding, assembly, degradation, and trafficking and thus function using proteomics, cell biology, electrophysiology, and animal model approaches.
2. Ameliorating ion channel misfolding diseases
We focus on diseases resulting from protein misfolding and thus reduced membrane protein surface expression and compromised function. This defective protein trafficking has been reported to result in many diseases, including neurodegenerative diseases and cardiovascular diseases.
We focus on developing multiple strategies to discover small molecules that enhance proper protein folding in cells to ameliorate diseases. We also explore the mechanism of action of these small molecules: how they alter the signaling pathways associated with the protein homeostasis network for disease intervention. Ultimately, we aim to develop novel therapeutic strategies for diseases associated with protein misfolding.
Publications
- Di XJ, Wang YJ, Cotter E, Wang M, Whittsette AL, Han DY, Sangwung P, Brown R, Lynch JW, Keramidas A, Mu TW, Proteostasis regulators restore function of epilepsy-associated GABAA receptors, Cell Chem Biol 2020, 27, https://doi.org/10.1016/j.chembiol.2020.08.012
- Wang YJ & TW Mu. Interactome Changes Quantified to Identify the ER Proteostasis Network to Fight Amyloid Diseases. Cell Chem Biol 26:909-910, 2019.
- Fu YL, B Zhang & TW Mu. LMAN1 (ERGIC-53) promotes trafficking of neuroreceptors. Biochem. Biophys. Res. Commun. DOI: 10.1016/j.bbrc.2019.02.053, 2019.
- Fu YL, DY Han, YJ Wang, XJ Di, HB Yu & TW Mu. Remodeling the endoplasmic reticulum proteostasis network restores proteostasis of pathogenic GABAA receptors. PLoS ONE 13:e0207948, 2018.
- Di XJ, YJ Wang, DY Han, YL Fu, AS Duerfeldt, BS Blagg & TW Mu. Grp94 Protein Delivers ?-Aminobutyric Acid Type A (GABAA) Receptors to Hrd1 Protein-mediated Endoplasmic Reticulum-associated Degradation. J. Biol. Chem. 291:9526-39, 2016.
- Han DY, XJ Di, YL Fu & TW Mu. Combining valosin-containing protein (VCP) inhibition and suberanilohydroxamic acid (SAHA) treatment additively enhances the folding, trafficking, and function of epilepsy-associated ?-aminobutyric acid, type A (GABAA) receptors. J. Biol. Chem. 290:325-37, 2015.