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Zhizhen(Chih-chen) Wang, Ph.D, Prof., CASM

Principal Investigator
National Laboratory of Biomacromolecules, IBP

Research Interests: Mechanism and regulation of oxidative protein folding in the endoplasmic reticulum, and their implication in diseases and aging

Email: chihwang@ibp.ac.cn

Tel: 010-64888500

Address: 15 Datun Road, Chaoyang District, Beijing, 100101, China

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1959 - 1964  Department of Biophysics, University of Science and Technology of China

1964 -           Institute of Biophysics, Chinese Academy of Sciences, Beijing, China,Research Assistant, Assistant Professor, Associate Professor, Professor;

1979 - 1981  Deutsches Wollforschungsinstitut, Aachen, Germany,Alexander von Humboldt fellow;

1981 - 1982  NIDDK, National Institutes of Health, Bethesda, USA, Fogarty Fellow;

1987 - 1988  City of Hope National Medical Center, Duarte, USA, Visiting Scientist;

1988 - 1991  Food and Drug Administration, Bethesda, USA, Visiting Scientist;

1991 - 1993  Dept. of Biochemistry, Alberta University, Edmonton, Canada, Research Associate;

1995.5-8       Abteilung Klinische Biochemie, Georg-August-University, Goettingen, Germany,Visiting Scientist;

1998.2-4       Dept. of Biochemistry, Hong Kong University of Science and Technology, Visiting Professor

1995 - 2001  Chinese delegate to the Federation of Asia and Oceania for Biochemistry and Molecular Biology;

2001              Elected into the membership of the Chinese Academy of Sciences (MCAS)

2005              Elected into the membership of the Academy of Sciences for the Developing World (TWAS).


Sciences Prize in Basic Sciences, Biology

The Science and Technology Advancement Award of the Ho Leung Ho Lee Foundation

The National Natural Science Award twice

The Academy Natural Science Award three times

Award for Outstanding Mentor in the Chinese Academy of Sciences three times

“Top 10 Women Elite in China”

Membership in Academies & Societies
Research Interests

Our group has been studying protein folding during past decades, particularly focusing on molecular chaperones and foldases. We proposed the hypothesis that “protein disulfide isomerase (PDI) is both an enzyme and a chaperone”. Then we systematically characterized the novel chaperone activity of protein disulfide isomerase and demonstrated the cooperative function of isomerase and chaperone activities in the folding of disulfide-containing proteins. Recently we are working on the mechanisms of oxidative protein folding and the regulation of ER redox homeostasis. Research interests include:

1.Mechanism of oxidative protein folding and its regulation in the ER

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 Ero1are different. We provided mechanistic insights intohow ER peroxidases(GPx7, GPx8 and Prx4) regulate oxidative protein folding. We are currently studying the new regulatory mechanisms of protein folding and ER redox homeostasis, especially on the post-translational level.

2. ER redox homeostasis and human health

By using multiple techniques for monitoring the ER redox fluctuation, we are studying the role of ER redox homeostasis in aging and age-related diseases, e.g. vascular diseases and cancers. We are aiming to identify the key enzymes and chaperones involved in ER redox-associated physiological and pathological processes. We will investigate the molecular mechanisms how these proteins regulate the ER redox homeostasis and affect aging and age-related diseases.

Selected Publications

1. Chen X, Zhang J, Liu P, Wei Y, Wang XE, Xiao J, Wang CC, Wang L* (2021) Proteolytic regulation of secretory pathway kinase Fam20C by site-1 protease. Proc Natl Acad Sci U S A, 118: e2100133118.

2. Wang L*, Yu J, Wang CC (2021) Protein disulfide isomerase is regulated in multiple ways: Consequences for conformation, activities and pathophysiological functions. BioEssays, Nov 6;e2000147. doi: 10.1002/bies.202000147. (invited review)

3. 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, e103841

(Highlighted by EMBO J 'News & Views'; Recommended by F1000Prime)

4. 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.

5. 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.

6. Zhang J, Zhu Q, Wang X, Yu J, Chen X, Wang J, Wang X, Xiao J, Wang CC, Wang L*. (2018) Secretory kinase Fam20C tunes endoplasmic reticulum redox via phosphorylation of Serine145 of Ero1α. EMBO J., e98699.

7. Fang J, Yang J, Wu X, Zhang G, Li T, Wang X, Zhang H, Wang CC, Liu GH*, Wang L*.(2018) Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7. Aging Cell, e12765.

8. 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.

9. Yang K, Li D, Wang XE, Liang J, Sitia R, Wang CC*, Wang X*. (2016) Crystal structure of the ERp44-peroxiredoxin 4 complex reveals the molecular mechanisms of thiol-mediated protein retention. Structure, 24:1755-1765.

10. Niu Y, Zhang L, Yu J, Wang CC*, 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(15):8283-94.

11. Wang L, Wang X, Wang CC*. (2015) Protein disulfide-isomerase, a folding catalyst and a redox-regulated chaperone. Free Radic. Biol. Med., 83:305-13.(invited review)

12. Zhang L, Niu Y, Zhu L, Fang J, Wang XE, Wang L*, 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(45):31188-31199.

13. Wang L*, Zhang L, Niu Y, Sitia R, Wang CC*. (2014) Glutathione peroxidase 7 utilizes hydrogen peroxide generated by Ero1α to promote oxidative protein folding. Antioxid. Redox Signal., 20(4):545-56. 

14. Wang C, Li W, Ren J, Fang J, Ke H, Gong W, Feng W*, Wang CC*. (2013) Structural insights into the redox-regulated dynamic conformations of human protein disulfide isomerase. Antioxid. Redox Signal., 19(1): 36-45.

15. 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.

16. Wang X, Wang L, Wang X, Sun F*, Wang CC*. (2012) Structural insights into the peroxidase activity and inactivation of human peroxiredoxin 4. Biochem. J., 441(1): 113-118.

17. Wang L, Zhu L, Wang CC*. (2011) The endoplasmic reticulum sulfhydryl oxidase Ero1β drives efficient oxidative protein folding with loose regulation. Biochem. J., 434, 113–121.

18. Wang C, Chen S, Wang X, Wang L, Wallis AK, Freedman RB*, 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(35): 26788-26797.

19. Wang L, Li SJ, Sidhu A, Zhu L, Liang Y, Freedman RB, 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(1): 199–206.

20. Wang L, Wang L, Vavassori S, Li S, Ke H, Anelli T, Degano M, Ronzoni R, Sitia R, Sun F*, Wang CC*. (2008) Crystal structure of human ERp44 shows a dynamic functional modulation by its carboxy-terminal tail. EMBO Rep., 9(7): 642–647.


(From Zhizhen(Chih-chen) Wang, December 3, 2021)


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