Principal Investigator, Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences.

Associate Research Scientist, Yale University School of Medicine, 2013-2015

Postdoctoral Fellow, National Institutes of Health, 2009-2012

Ph.D., Institute of Biophysics, Chinese Academy of Sciences, 2004-2009

B.S., Shandong University, 2000-2004

Neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis, Alzheimer’s disease, and Parkinson’s disease, are devastating lethal diseases that affect a large number of individuals in the aging population worldwide. The pathological accumulation of specific proteins with aberrant conformation plays a crucial role in driving the progressive dysfunction of specific neurons in selective brain regions in these diseases. The failure of protein quality control and degradation systems, that usually are concomitant with aging, are largely responsible for promoting the pathological deposition of these diseases-causing proteins. Zhang’s research group aims to elucidate the cellular mechanisms involved in the degradation of detrimental misfolded proteins. Our research will contribute significantly to the understanding of the age-onset decline of proteostasis and thus help to combat neurodegenerative diseases and aging.

1. Understanding the mechanistic basis of misfolded protein degradation and deposition pathway.

The eukaryotic ER maintains protein homeostasis by eliminating unwanted proteins by the ER-associated degradation (ERAD) pathway. Despite advances in past decades, many fundamental questions remain to be answered. Zhang’s research will be focused on several aspects of aberrant protein degradation that range from mechanistic studies in vitro to analysis of its importance in cells and animals. The long-term goal of our lab is to understand the principles that govern the clearance and deposition of misfolding-prone proteins, and to identify strategies that could reduce the burden of damaged proteins for cells and organisms.

2. Identifying unknown components that regulate cellular protein homeostasis under pathophysiological conditions.

To date, protein degradation is often examined using artificial substrates or disease relevant mutant proteins. Due to the presence of limited number of endogenous substrates, the importance of protein destruction under physiological conditions has been poorly understood. By using multiple genomic, biochemical, and proteomic strategies, Zhang’s research group is currently investigating ER protein abundance at various conditions in cells (e.g., with elevated or decreased protein degradation capacity). This will lead to discovery of new protein components (e.g., those prone to be misfolded and degraded) that could be involved in ageing, and thus will uncover the interplay of protein degradation and other cellular pathways.

3. Mechanism underlying ER stress response and neurodegenerative diseases.

Unfolded protein response (UPR) is a key quality control system that senses ER stress signals and initiates global changes in transcription and translation to maintain ER homeostasis. It is now evident that UPR functions in various physiological conditions, and are master regulators of human disorders including diabetes, cancer, aging, and neurodegeneration. However, little is known about how UPR is modulated under various physiological conditions, such as increased protein synthesis, elevated levels of lipids, and high or low hexosamine levels. Zhang’s lab is performing a genome wide screen for components that are involved in the Ire1-, PERK-, andATF6-UPR branches in mammalian cells. These studies will identify novel factors that are involved in the ER stress response in mammalian cells, and will provide promising therapeutic targets for the treatment of human diseases, such as diabetes, cancer and aging.

Representative publications (*corresponding author)

1.    Ji J, Cui MK, Zou R, Wu MZ, Ge MX, Li J, & Zhang ZR*. (2024) An ATP13A1-assisted topogenesis pathway for folding multi-spanning membrane proteins. Molecular Cell, 84, 1917-1931

²  Highlighted with commentary by Ramanujan Hegde: Getting Membrane Proteins into Shape. Molecular Cell, 84,1821-1823

2.    Hu X, Zou R, Zhang Z, Ji J, Li J, Huo XY, Liu D, Ge MX, Cui MK, Wu MZ, Li ZP, Wang Q, Zhang X & Zhang ZR*. (2023) UBE4A catalyzes NRF1 ubiquitination and facilitates DDI2-mediated NRF1 cleavage. Biochim Biophys Acta Gene Regul Mech. 1866: 194937

3.    Wang L, Li J, Wang Q, Ge MX, Ji J, Liu D, Wang Z, Cao Y, Zhang Y & Zhang ZR*. (2022) TMUB1 is an endoplasmic reticulum-resident escortase that promotes p97-mediated extraction of membrane proteins for degradation. Molecular Cell 82, 3453-3467

4.    Hu X, Wang L, Wang Y, Ji J, Li J, Wang Z, Li C, Zhang Y & Zhang ZR*. (2020) RNF126-mediated reubiquitination is required for proteasomal degradation of p97-extracted membrane proteins. Molecular Cell 79, 320-331

²  Highlighted with commentary by Claudia Schmidt and Alexander Stein: Off and On Again: De- and Reubiquitination during Membrane Protein Degradation. Molecular Cell, 79,203-204

5.    Shi J, Hu X, Guo Y, Wang L, Ji J, Li J & Zhang ZR*. (2019) A technique for delineating the unfolding requirements for substrate entry into retrotranslocons during endoplasmic reticulum-associated degradation. J Biol Chem. 294, 20084-20096. Recommended in Faculty of 1000

6.    Zhang ZR*, Bonifacino JS & Hegde RS*. (2013) Deubiquitinases sharpen substrate discrimination during membrane protein degradation from the ER. Cell 154, 609-622,

²  Highlighted with commentary by Jeffrey Brodsky: Just a trim, please: refining ER degradation through deubiquitination. Cell, 154,479-481

Other publications (#first author):

1.    Zhang M, Wang Z, Zhao Q, Yang Q, Bai J, Yang C, Zhang ZR, Liu Y*. (2024) USP20 deubiquitinates and stabilizes the reticulophagy receptor RETREG1/FAM134B to drive reticulophagy. Autophagy. Online ahead of print.

2.    Hou X, Zhang X, Zou H, Guan M, Fu C, Wang W, Zhang ZR, Geng Y* & Chen Y*. (2023) Differential and substrate-specific inhibition of γ-secretase by the C-terminal region of ApoE2, ApoE3, and ApoE4. Neuron. 111, 1898-1913

3.    Liang W, Qi W, Geng Y, Wang L, Zhao J, Zhu K, Wu G, Zhang ZR, Pan H, Qian L & Yuan J*. (2021) Necroptosis activates UPR sensors without disrupting their binding with GRP78. Proc Natl Acad Sci USA. 118 (39): e2110476118.

4.    Coelho JPL, Stahl M, Bloemeke N, Meighen-Berger K, Alvira CP, Zhang ZR, Sieber SA & Feige MJ*. (2019) A network of chaperones prevents and detects failures in membrane protein lipid bilayer integration. Nat Commun. 10, 672.

5.    Plumb R^#, Zhang ZR^#, Appathurai S & Mariappan M*. (2015) A functional link between the co-translational protein translocation pathway and the UPR. eLife 4, e07426 (#co-first author)

6.    Park SY, Waheed AA, Zhang ZR, Freed EO & Bonifacino JS*. (2014) HIV-1 Vpu accessory protein induces caspase-mediated cleavage of IRF3 transcription factor. J. Biol. Chem. 289, 35102-35110

7.    Moran C, Kinsella GK, Zhang ZR, Perrett S & Jones GW*. (2013) Mutational Analysis of Sse1 (Hsp110) Suggests an Integral Role for this Chaperone in Yeast Prion Propagation In Vivo. G3: Genes, Genomes, Genetics 3, 1409-1418

8.    Emerman AB, Zhang ZR, Chakrabarti O & Hegde RS*. (2010). Compartment-restricted biotinylation reveals novel features of prion protein metabolism in vivo. Mol. Biol. Cell 21, 4325-4337

9.    Zhang C, Jackson A, Zhang ZR, Han Y, Yu S, He RQ & Perrett S*. (2010). Amyloid-Like aggregates of the yeast prion protein Ure2 enter vertebrate cells by specific endocytotic pathways and induce apoptosis. PLoS ONE 5, e12529

10.  Zhang ZR^#& Perrett S*. (2009). Novel glutaredoxin activity of the yeast prion protein Ure2 reveals a native-like dimer within fibrils. J. Biol. Chem. 284, 14058-14067

11.  Wang XY, Zhang ZR & Perrett S*. (2009). Characterization of the activity and folding of the glutathione transferase from Escherichia coli and the roles of residues Cys10 and His106. Biochem. J. 417, 55-64

12.  Zhang ZR^#, Bai M, Wang XY, Zhou JM & Perrett S*. (2008). "Restoration" of glutathione transferase activity by single-site mutation of the yeast prion protein Ure2. J. Mol. Biol. 384, 641-651

13.  Lian HY, Zhang H, Zhang ZR, Loovers HM, Jones GW, Rowling PJ, Itzhaki LS, Zhou JM & Perrett S*. (2007). Hsp40 interacts directly with the native state of the yeast prion protein Ure2 and inhibits formation of amyloid-like fibrils. J. Biol. Chem. 282, 11931-11940