deguangliang(at)gmail.com
The Liang laboratory at CIMR studies the molecular regulation and biological function of phospholipid (PL) metabolism pathways (e.g., PL de novo synthesis, remodeling, transport, etc.) under different physiological and pathological conditions. The PL profile, encompassing subclass composition and saturation levels, is highly diverse among cell types, organelles, and even membrane subdomains, and is dynamically regulated. Intriguingly, although increasing polyunsaturated fatty acids (PUFA) content in the PL can fulfill numerous cellular functions through improving the fluidity of the cellular membrane, it also increases the intrinsic susceptibility to ferroptosis, a form of regulated cell death caused by iron-mediated uncontrolled peroxidation of PL-PUFAs. Ferroptosis has been implicated in various diseases, including cancer, neurodegeneration, and ischemic organ injury. It is still largely unknown how cells dynamically sense and adjust PL profiles in response to different stimulus and maintain a balance between cellular function and ferroptosis vulnerability.
In a previous CRISPR activation screen, MBOAT1/2 had been identified as novel ferroptosis suppressors which inhibited ferroptosis via PL remodeling process in an ER/AR regulated manner in hormone receptor positive breast cancer and prostate cancer, respectively. (Liang et al., Cell, 2023). Building on these findings, we will utilize a combination of approaches including biochemistry, chemical biology, high-throughput screening, lipidomics, etc. to investigate how MBOAT1/2 suppress ferroptosis through precisely regulating PE-PUFAs synthesis in subcellular level. We will use cellular and animal models to further demonstrate the function of MBOAT1/2. We will also try to identify other novel ferroptosis regulators via PL metabolism pathways by optimized high throughput screening approaches.
We hypothesize that there is some checkpoint mechanism to precisely regulate PL profiles to achieve a balance between adequate cellular function and ferroptosis vulnerability. We will investigate the cellular sensing mechanism for PL saturation level and the feedback regulation of PL metabolism pathways to dynamically adjust the PL profiles in response to different stress conditions. We will utilize subcellular lipidomic analysis to measure the dynamic change of PL profiles, and employ RNA-seq, ATAC-seq, proteomic analysis, etc. to identify potential PL metabolism-related genes that are differentially regulated in response to various cellular stimulus.
3. Dynamic regulation of PL metabolism in neuron aging and degeneration
Ferroptosis has been implicated in the progression of neurodegenerative diseases, possibly due to iron overload during aging. However, little is known about the role of aberrant PL metabolism in neuron aging and degeneration. We will establish iPSC-derived neurons (iN) to track changes of PL profiles during neuron aging and degeneration. We will try to identify PL metabolism-related genes which are deregulated during neuron aging and degeneration. We will also perform whole-genomic CRISPR screen with iN cells to identify neuron-specific negative and positive regulators of ferroptosis.
Liang D, Feng Y, Zandkarimi F, Wang H, Zhang Z, Kim J, Cai Y, Gu W, Stockwell B R, and Jiang X. Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones. Cell, 2023, 186: 2748-64 e22. DOI: 10.1016/j.cell.2023.05.003
Liang D, and Jiang X. START smuggling CoQ to fight ferroptosis. Nature Cell Biology, 2023, 25: 207-8. DOI: 10.1038/s41556-022-01044-1
Liang D, Minikes A M, and Jiang X. Ferroptosis at the intersection of lipid metabolism and cellular signaling. Molecular Cell, 2022, 82: 2215-27. DOI: 10.1016/j.molcel.2022.03.022
Liang D, Deng L, and Jiang X. A new checkpoint against ferroptosis. Cell Research, 2020, 30: 3-4. DOI: 10.1038/s41422-019-0258-0
Liang D*, Hu H*, Li S, Dong J, Wang X, Wang Y, He L, He Z, Gao Y, Gao S J, and Lan K. Oncogenic herpesvirus KSHV Hijacks BMP-Smad1-Id signaling to promote tumorigenesis. PLoS Pathogens, 2014, 10: e1004253. DOI: 10.1371/journal.ppat.1004253. (* equal contribution)
Liang D, Lin X, and Lan K. Looking at Kaposi's Sarcoma-Associated Herpesvirus-Host Interactions from a microRNA Viewpoint. Frontiers of Microbiology, 2011, 2: 271. DOI: 10.3389/fmicb.2011.00271
Hu H*, Dong J*, Liang D*, Gao Z, Bai L, Sun R, Hu H, Zhang H, Dong Y, and Lan K. Genome-Wide Mapping of the Binding Sites and Structural Analysis of Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 2 Reveal that It Is a DNA-Binding Transcription Factor. Journal of Virology, 2016, 90: 1158-68. DOI: 10.1128/jvi.01392-15. (* equal contribution)
10 Xitoutiao, Youanmen Wai, Fengtai District, Beijing 100069, China
010-86738999
cimr@cimrbj.ac.cn
中文
