The endoplasmic reticulum (ER) is the largest part of the endomembrane system in eukaryotic cells, and is the factory for protein folding and processing. The ER contains a ‘quality control’ system, which is comprised of a large number of folding enzymes and chaperones, to maintain the protein homeostasis (proteostasis) in the ER. The ER provides an optimal redox environment for the correct folding of disulfide-containing proteins (e.g. secretory and membrane proteins), namely oxidative protein folding. The relationship between ER redox homeostasis (redoxtasis) and human health has attracted considerable attention in recent years. Dr. Lei Wang worked on the reconstitution of ER oxidative protein folding system during his Ph.D study, together with his mentor Prof. Chih-chen Wang. After graduation, he preferred to stay in the lab and extend his work to the regulation of ER redoxtasis and human health.
Recent Work Progresses：
1. Mechanism of oxidative protein folding and its regulation in the ER
Protein-disulfide isomerase (PDI) and sulfhydryl oxidase Ero1 constitute the pivotal pathway for oxidative protein folding in the ER. We succeeded to constitute the human Ero1/PDI oxidative folding system, and revealed the different working mechanisms of human and yeast Ero1/PDI system. We also demonstrated that the modes for PDI as an efficient regulator and a specific substrate of Ero1 are different. We found that the ER peroxidase GPx7 can directly utilize Ero1-generated peroxide to oxidized PDI and promote oxidative protein folding, providing mechanistic insights into the Ero1/GPx7/PDI triad. We are currently studying the new regulatory mechanisms of protein folding and ER redoxtasis, especially on the post-translational level.
2. ER redoxtasis and human health
By using multiple techniques for monitoring the ER redox fluctuation, we are studying how the cell senses the over-oxidation signal in the ER due to the overload of oxidative protein folding, and how the antioxidant response is launched to maintain the redoxstasis in the ER. We are also curious about the role of ER redoxtasis in aging and age-related diseases. To identify the key enzymes and chaperones involved in these redoxtasis-associated physiological and pathological processes will be beneficial to the discovery of small molecule drugs for promoting human health.
Selected publications(*Corresponding/Senior author)
1. Yu J, Li T, Liu Y, Wang X, Zhang J, Wang Xe, Shi G, Lou J, Wang L, Wang CC, Wang L* (2020) Phosphorylation switches protein disulfide isomerase activity to maintain proteostasis and attenuate ER stress. EMBO J 39: e103841
2. Fan F, Zhang Y, Huang G, Zhang Q, Wang CC, Wang L*, Lu D* (2019) AtERO1 and AtERO2 exhibit differences in catalyzing oxidative protein folding in the ER. Plant Physiol 180:2022-2033.
3. Zhang Y, Li T, Zhang L, Shangguan F, Shi G, Wu X, Cui Y, Wang Xe, Wang X, Liu Y, Lu B, Wei T, Wang CC, Wang L* (2019) Targeting the functional interplay between endoplasmic reticulum oxidoreductin-1α and protein disulfide isomerase suppresses the progression of cervical cancer. EBioMedicine 41:408-419.
4. Wu X, Zhang L, Miao Y, Yang J, Wang X, Wang CC, Feng J*, Wang L* (2019) Homocysteine causes vascular endothelial dysfunction by disrupting endoplasmic reticulum redox homeostasis. Redox Biol 20: 46-59.
5. Zhang J, Zhu Q, Wang Xe, Yu J, Chen X, Wang J, Wang X, Xiao J, Wang CC, Wang L* (2018) Secretory kinase Fam20C tunes endoplasmic reticulum redox state via phosphorylation of Ero1α. EMBO J 37: e98699.
6. Fang J, Yang J, Wu X, Zhang G, Li T, Wang Xe, Zhang H, Wang CC, Liu GH*, Wang L* (2018) Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7. Aging Cell 17: e12765.
7. Li H, Yang K, Wang W, Niu Y, Li J, Dong Y, Liu Y, Wang CC, Wang L*, Liang H* (2018) Crystal and solution structures of human protein disulfide isomerase-like protein of the testis (PDILT) provide insight into its chaperone activity. J Biol Chem 293, 1192-1202.
8. Fan F, Zhang Y, Wang S, Han Y, Wang L*, Lu D* (2018) Characterization of the oxidative protein folding activity of a unique plant oxidoreductase, Arabidopsis protein disulfide isomerase-11. Biochem Biophys Res Commun 495:1041-1047.
9. Niu Y, Zhang L, Yu J, Wang CC* and Wang L* (2016) Novel roles of the non-catalytic elements of yeast protein-disulfide isomerase in its interplay with endoplasmic reticulum oxidoreductin 1. J Biol Chem 291:8283-8294.
10. Wang L, Wang X and Wang CC* (2015) Protein disulfide-isomerase, a folding catalyst and a redox-regulated chaperone. Free Radical Bio Med 83:305-313.(invited review)
11. Zhang L, Niu Y, Zhu L, Fang J, Wang Xe, Wang L* and Wang CC* (2014) Different interaction modes for protein-disulfide isomerase (PDI) as an efficient regulator and a specific substrate of endoplasmic reticulum oxidoreductin-1α (Ero1α). J Biol Chem 289:31188-31199.
12. Wang L*, Zhang L, Niu Y, Sitia R and Wang CC* (2014) Glutathione peroxidase 7 utilizes hydrogen peroxide generated by Ero1α to promote oxidative protein folding. Antioxid Redox Signal 20: 545-556.
13. Wang C, Yu J, Huo L, Wang L, Feng W*, Wang CC* (2012) Human protein disulfide isomerase is a redox-regulated chaperone activated by oxidation of domain a'. J Biol Chem 287: 1139-1149.
14. Wang L, Zhu L and Wang CC (2011) The Endoplasmic Reticulum Sulphydryl Oxidase Ero1β Drives Efficient Oxidative Protein Folding with Loose Regulation. Biochem J 434:113-121.
15. Wang C, Chen S, Wang X, Wang L, Wallis AK, Freedman RB* and Wang CC* (2010) Plasticity of human protein disulfide isomerase: evidence for mobility around the X-linker region and its functional significance. J Biol Chem 285: 26788-26797.
16. Wang L, Li SJ, Sidhu A, Zhu L, Liang Y, Freedman RB, and Wang CC* (2009) Reconstitution of human Ero1-Lα/protein disulfide isomerase oxidative folding pathway in vitro: position-dependent differences in role between the a and a' domains of protein disulfide isomerase. J Biol Chem 284: 199-206.
17. Wang L, Wang L, Vavassori S, Li S, Ke H, Anelli T, Degano M, Ronzoni R, Sitia R, Sun F*, and Wang CC* (2008) Crystal structure of human ERp44 shows a dynamic functional modulation by its carboxy-terminal tail. EMBO Rep 9: 642-647.
Conference Presentations
1. The 17th Chinese Biophysics Congress, Tianjin, China (invited talk) Aug. 2019
2. The 14th European ER & Redox meeting, Herrsching, Germany (oral presentation) May, 2019
3. EMBO workshop: Membrane Shaping and Remodeling by Proteins, Xiuning, China (oral presentation) Apr. 2019
4. EMBO workshop “Endoplasmic Reticulum Function in Health and Disease”, Lucca, Italy (poster presentation) Oct. 2018
5. The 6th Symposium of Chinese Protein Society, Guangzhou, China (oral presentation) Sep. 2017
6. The 1st International Conference for Cancer Metabolism and Therapy, Dalian, China (oralpresentation)Oct. 2016
7. The 5th Symposium of Chinese Protein Society, Jining, China (oral presentation)Oct. 2015
8. VIIth Cell Stress Society International Congress on Stress and Health, Huangshan, China(invited talk)Sep. 2015
9. The 12th European ER & Redox meeting, Venice, Italy (oral presentation) Apr. 2015
10. The 3rd International Supramolecular System Symposium, Changchun, China(invited talk) Aug. 2014
11. The 3rd National Conference of Biophysical Chemistry, Qingdao, China(oralpresentation)Jul.2014
12. The 4th Symposium of Chinese Protein Society, Hefei, China (oral presentation) Oct. 2013
13. The 11th European ER & Redox meeting, Coventry, UK (oral presentation) Apr. 2013
14. “Cold Spring Harbor Asia Meeting: Protein Homeostasis in Health and Disease”, Suzhou, China (invited talk) Sep. 2011
15. “The Inaugural Hsien Wu and Ray Wu Symposia”, Beijing, China (invited talk)Jul. 2011
16. The 10th European ER & Redox meeting, Munich, Germany (oral presentation) Apr. 2011
17. The 21st IUBMB and 12th FAOBMB International Congress of Biochemistry and Molecular Biology, Shanghai, China (poster presentation)Aug. 2009
18. The 6th Asian Biophysics Association Symposium, Hong Kong, China (oral presentation) Jan. 2009
19. The 2nd Symposium of Chinese Protein Society, Yantai, China (oral presentation)Jul. 2008
From Lei Wang, Mar 10, 2020
