Proteostasis maintenance of membrane proteins in health and disease
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 neurodegerative diseases 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 signicantly 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 inhibiory ion channels in the mamalian central nervous systems. Loss of their function leads to idiopathic epilepies.
- Human Ether-a-go-go-Related Gene (hERG) channesl (gene name: KCNH2). Loss of their function leads to long-QT syndrome.
We explore how molecular chaperones, folding enzymes, ERAD factors, and trafficking factors, coordinate to facilitate membrane proein 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.
Proteostasis maintenance of GABAA receptors
Ion channel proteins maintain a delicate balance between protein synthesis, folding, assembly, trafficking and degradation. Mutant membrane proteins are subjected to excessive endoplasmic-reticulum associated degradation. Molecular chaperones and ERAD factors play a key role in regulating their proteostasis.
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 control their folding, assembly, degradation, and trafficking and thus function using proteomics, cell biology, electrophsiology, and animal model approaches.
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.
- Di XJ, Wang YJ, Han DY, Fu YL, Duerfeldt AS, Blagg BSJ, and Mu TW, Grp94 Delivers gamma-aminobutyric Acid Type A (GABAA) Receptors to Hrd1-Mediatd Endoplasmic Reticulum-Associated Degradation. J. Biol. Chem., doi:10.1074/jbc.M115.705004. 2016
- Fu YL, Wang YJ, Mu TW, Proteostasis Maintenance of Cys-Loop Receptors. Adv Protein Chem Struct Biol. 103:1-23, 2016.
- Han DY, BJ Guan, YJ Wang, M Hatzoglou & TW Mu. L-type Calcium Channel Blockers Enhance Trafficking and Function of Epilepsy-associated ?1(D219N) Subunits of GABAA Receptors. ACS Chem. Biol. 10:2135-48, 2015.
- 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.
- Wang YJ, XJ Di & TW Mu. Using pharmacological chaperones to restore proteostasis. Pharmacol. Res. 83:3-9, 2014.
- Wang YJ, DY Han, T Tabib, JR Yates & TW Mu. Identification of GABA(C) receptor protein homeostasis network components from three tandem mass spectrometry proteomics approaches. J. Proteome Res. 12:5570-86, 2013.