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Faculty

Members of CAS, CAE
National Outstanding Young Scientists Award
Principal Investigators
 
Address: 320 Yue Yang Road, Shanghai 200031, P.R. China
Tel: 86-21-54920000
Fax: 86-21-54921011
Email: sibcb@sibs.ac.cn
Website: www.sibcb.ac.cn
 
Principal Investigators
 
XU Chenqi
Ph.D., Professor
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China.
Email: cqxu@@sibcb.ac.cn
Lab homepage: xulab.sibcb.ac.cn

Research Areas
lymphocyte and disease

Research Interests

In the past years, the Xu lab has developed cutting-edge biochemical and biophysical tools to study transmembrane signaling of T-cell receptor, co-stimulatory and co-inhibitory receptors. In addition, we also study lipid metabolism of T cells and have demonstrated the clinical potential of lipid-based immunotherapy.

Immunoreceptor signaling
A large number of receptors expressed on T cell surface orchestrate precisely to regulate adaptive immunity. These receptors can be classified to antigen receptor (TCR), co-stimulatory receptors (CD28 and others) and co-inhibitory receptors (PD-1 and others). Our group is interested in understanding the transmembrane signaling and protein regulation mechanisms of these receptors.

Immunoreceptors on T cell surface normally engage with membrane-anchored ligands and elicit ligand-dependent signaling through phosphorylation of tyrosine-based motifs. It is well known that tyrosine phosphorylation of immunoreceptors are regulated by kinases and phosphatases, but less is known about the role of neighboring lipid molecules. We find that acidic phospholipids can ionically interact with basic residues in juxtamembrane regions of immunoreceptors to sequester tyrosine phosphorylation sites within the membrane bilayer and therefore avoid spontaneous activation. Such an ionic protein-lipid interaction is dynamic and can be influenced by local charge, mechanical force, membrane rigidity and curvature. We find that Ca2+ influx following T cell activation not only regulates downstream signaling but also modulates TCR and CD28 phosphorylation through the disruption of ionic protein-lipid interaction. Mechanistically, influxed Ca2+ ions transiently accumulate at channel pore region and directly interact with phosphate groups of acidic phospholipids to neutralize negative charges, which is specific and reversible. In comparison, other abundant cations in cytosol, such as Mg2+ and K+, show much weaker lipid binding due to their chemical properties. Importantly, this lipid/Ca2+ regulation is generally applicable to a diverse range of receptors like TCR, CD28 and LFA1 in T cells as well as IgG-BCR in B cells (Cell 2008, Nature 2013, Nat Comm 2015, Nat Rev Immunol 2016, Nat Struct Mol Bio 2017, PLOS Bio 2018).

Reciprocal regulation of TCR signaling by acidic phospholipids and Ca2+.
(a)Acidic glycerophospholipids sequester immunoreceptor tyrosine-based activation motifs (ITAMs) of CD3e and CD3z cytoplasmic domains within the membrane bilayer, thus preventing the spontaneous T cell receptor phosphorylation and signaling in quiescent T cells. Upon antigen stimulation, multiple factors regulate the dissociation of ITAMs from the membrane to permit signaling. (b) Nuclear magnetic resonance structure of membrane-bound CD3eITAM. The key tyrosine residues insert deeply into the membrane interior. PS, phosphatidylserine; TCR, T cell receptor. (Cell 2008, Nature 2013, Nat Rev Immunol 2016)

In addition to immunoreceptor phosphorylation process, another interest in the lab is to understand the basic biology of co-inhibitory receptors, in particular PD-1. Despite of its clinical importance, PD-1 signaling is still poorly understood. Key questions, for example, why PD-1 is abnormally upregulated in tumor microenvironment and how PD-1 suppresses T cell activation, remain to be addressed. We recently discover a degradation mechanism of PD-1 (Nature 2018). Surface PD-1 molecules are under constant internalization, and a E3 ligase FBXO38 mediates K48-linked polyubiquitination of internalized PD-1 that leads to proteasome degradation. This degradation mechanism is deficient in tumor infiltrating T cells because of low transcription level of Fbxo38 gene. Administration of IL2 is able to rescue FBXO38 expression to degrade PD-1 and reinvigorate T cell antitumor function. As one of the first-generation immunotherapy medicines, IL2 has already been approved to treat melanoma and kidney cancer. Thus, it should be of high interest to reconsider IL2’s application in different types of cancer. We will continue to investigate the signaling and regulation mechanisms of PD-1 under diverse disease contexts.


Degradation of PD-1 in T cells. Surface PD-1 molecules can be internalized, ubiquitinated and degraded in proteasome. FBXO38 mediates K48-linked polyubiquitination of internalized PD-1. In tumor infiltrating T cells, Fbxo38 transcription is downregulated because of chronic antigen exposure and deficiency of CD28 and IL2 signaling. IL2 therapy can rescue FBXO38 expression in TIL through STAT5 activation, which in turn downregulates PD-1 surface level and reinvigorates T-cell antitumor activity. (Nature 2018)

Lipid metabolism
We recently start to explore the less-known immunometabolism field. Tumor bed is usually considered as a metabolic desert where T cells suffer from persistent nutrition deficiency stress. Moreover, some cancer-secreted metabolites were reported to exert diverse immune suppression functions. Hence, reprogramming T-cell metabolism would be necessary to improve cell survival and effector function against cancer cells. Moreover, metabolic regulation can be combined with signaling regulation to achieve better therapeutic effect. We found that inhibition of ACAT1, a key cholesterol esterification enzyme, augments TCR signaling and promotes immunological synapse maturation in CD8+ T cells. A pharmacological ACAT inhibitor (Avasimibe), which was previously used for cardiovascular diseases, potentiates the antitumor response of CD8+ T cells in preclinical models. A combined therapy of Avasimibe and anti-PD-1 shows better efficacy than monotherapies in controlling tumor progression, because the two reagents act through different mechanisms (Nature 2016). Following this work, we will keep exploring the complicated network of lipid metabolism and develop more lipid-based immunotherapies.

Metabolic regulation of antitumor immunity. Metabolic stress in tumor microenvironment is one of the major causes of T-cell exhaustion. Inhibition of a cholesterol esterification enzyme ACAT1 reprograms cholesterol metabolism in T cells, leading to higher cholesterol level at the plasma membrane. Elevated cholesterol then contributes to better TCR clustering and immunological synapse formation. ACAT1 inhibition therefore promotes TCR signaling and T-cell killing function. An old drug (Avasimibe), targeting ACAT1 for cardiovascular disease, has been repurposed to treat cancer in our study. Avasimibe acts as a good antitumor reagent by itself or in combination with PD-1 blockade antibody. (Nature 2016)

Future directions
In the next five years, the Xu lab will mainly focus on the following subjects:
1.Lipid metabolic programs of T-cell subsets under different physiological and pathological conditions.
2.Functional roles of lipid metabolism in T-cell antitumor immunity.
3.Identification of T-cell “metabolic checkpoints” for cancer immunotherapy.
4.Immunoreceptor regulation and signaling

Selected Publications

( #first author, *corresponding author )
  1. Guo J, Xu C*Screening for the next-generation T cell therapiesCancer Cell, 37(5): 627-629, 2020.
  2. Fan Z#, Tian Y#, Chen Z, Liu L, Zhou Q, He J, Coleman J, Dong C, Li N, Huang J, Xu C, Zhang Z, Gao S, Zhou P*, Ding K*, Chen L*Blocking interaction between SHP2 and PD-1 denotes a novel opportunity for developing PD-1 inhibitors. EMBO molecular medicine, e11571, 2020.
  3. He X, Xu C*, PD-1: A Driver or Passenger of T Cell Exhaustion? Molecular Cell, 77(5): 930-931, 2020.
  4. Huang B, Song B, Xu C*Cholesterol metabolism in cancer: mechanisms and therapeutic opportunitiesNature Metabolism, 2: 132-141, 2020.
  5. Xu X#, Li H#Xu, C*Structural understanding of T cell receptor triggering. Cellular & Molecular Immunology, 17(3): 193-202, 2020.
  6. Li H*, Yan C, Guo J, Xu C*. Ionic protein–lipid interactions at the plasma membrane regulate the structure and function of immunoreceptors. Advances in Immunology, 144 pp 65-85, 2019.
  7. Wu P, Zhang T, Liu B, Fei P, Cui L, Qin R, Zhu H, Yao D, Martinez R, Hu W, An C, Zhang Y, Liu J, Shi J, Fan J, Yin W, Sun J, Zhou C, Zeng X, Xu C, Wang J, Evavold B, Zhu C, Chen W*, Lou J*. Mechano-regulation of Peptide-MHC Class I Conformations Determines TCR Antigen Recognition. Molecular Cell. 73(5):1015-1027, 2019.
  8. Meng X#, Liu X#, Guo X, Jiang S, Chen T, Hu Z, Liu H, Bai Y, Xue M, Hu R, Sun SC, Liu X, Zhou P, Huang X, Wei L, Yang W, Xu C*. FBXO38 mediates PD-1 ubiquitination and regulates anti-tumour immunity of T cells. Nature. 564 (7734): 130-135, 2018.
  9. Guo J#, Zhang Y#, Li H#, Chu H#, Wang Q, Jiang S, Li Y, Shen H, Li G*, Chen J*, Xu C*. Intramembrane ionic protein-lipid interaction regulates integrin structure and function. PLoS Biology, 16(11):e2006525, 2018.
  10. Chen X#, Sun X#, Yang W#, Yang B#, Zhao X, Chen S, He L, Chen H, Yang C, Xiao L, Chang Z, Guo J, He J, Zhang F, Zheng F, Hu Z, Yang Z, Lou J, Zheng W, Qi H, Xu C, Zhang H, Shan H, Zhou XJ, Wang Q, Shi Y, Lai L, Li Z*, Liu W*. An autoimmune disease variant of IgG1 modulates B cell activation and differentiation. Science. 362 (6415): 700-705, 2018.
  11. Wang J, Yan C, Xu C, Chua B, Li P*, Chen F*. Polybasic RKKR motif in the linker region of lipid droplet (LD)-associated protein CIDEC inhibits LD fusion activity by interacting with acidic phospholipids. Journal of Biological Chemistry. 293(50):19330-19343, 2018.
  12. Xu C, Xie H, Guo X, Gong H, Liu L, Qi H, Xu C, Liu W*. A PIP2-derived amplification loop fuels the sustained initiation of B cell activation. Science Immunology, 2(17), 2017
  13. Bietz A#, Zhu H#, Xue M, Xu C*. Cholesterol Metabolism in T Cells. Frontiers in Immunology, 8:1664, 2017
  14. Yang W#, Pan W#, Chen S#, Trendel N#, Jiang S#, Xiao F, Xue M, Wu W, Peng Z, Li X, Ji H, Liu X, Jiang H, Wang H, Shen H, Dushek O*, Li H*, Xu C*. Dynamic regulation of CD28 conformation and signaling by charged lipids and ions. Nature Structural & Molecular Biology, 24(12), pp 1081-1092, 2017.
  15. Wang H, Wang S, Li C, Li H, Mao Y, Liu W, Xu C*, Long D*. Probing Transient Release of Membrane-Sequestered Tyrosine-Based Signaling Motif by Solution NMR Spectroscopy. The Journal of Physical Chemistry Letters, 8(16), pp 3765-3769, 2017.
  16. Li L#, Guo X#, Shi X#, Li C#, Wu W, Yan C, Wang H, Li H, Xu C*. Ionic CD3-Lck interaction regulates the initiation of T-cell receptor signaling. Proceedings of the National Academy of Sciences of the United States of America (Plus), 114(29), pp E5891-E5899, 2017.
  17. Guo X#, Yan C#, Li H#, Huang W#, Shi X, Huang M, Wang Y, Pan W, Cai M, Li L, Wu W, Bai Y, Zhang C, Liu Z, Wang X, Zhang F X, Tang C, Wang H, Liu W, Ouyang B, Catherine C Wong, Cao Y*, Xu C*. Lipid-dependent conformational dynamics underlie the functional versatility of T-cell receptor. Cell Research, 27(4), pp 505-525, 2017.
  18. Xu L#, Xia M#, Guo J#, Sun X#, Li H, Xu C, Gu X, Zhang H, Yi J, Fang Y, Xie H, Wang J, Shen Z, Xue B, Sun Y, Meckel T, Chen Y, Hu Z, Li Z*, Xu C*, Gong H*, Liu W*. Impairment on the lateral mobility induced by structural changes underlies the functional deficiency of the lupus-associated polymorphism FcγRIIB-T232. The Journal of Experimental Medicine, 213(12), pp 2707-2727, 2016.
  19. Wu W, Shi X, Xu C*. Regulation of T cell signalling by membrane lipids. Nature Reviews Immunology, 16(11), pp 690-701, 2016.
  20. Liu W*, Wang H, Xu C*. Antigen Receptor Nanoclusters:Small Units with Big Functions. Trends in Immunology, 37(10), pp 680-689, 2016.
  21. Yang W#, Bai Y#, Xiong Y, Zhang J, Chen S, Zheng X, Meng X, Li L, Wang J, Xu C, Yan C, Wang L, Chang C, Chang T, Zhang T, Zhou P Song B, Liu W, Sun S, Liu X, Li B*, Xu C*. Potentiating the anti tumour response of CD8+ T cells by modulating cholesterol metabolism. Nature, 531(7596), pp 651-655, 2016.
  22. Cui Y#, Chen X#, Zhang J, Sun X, Liu H, Bai L, Xu C, Liu X*. Uhrf1 Controls iNKT Cell Survival and Differentiation through the Akt-mTOR Axis. Cell Reports, 15(2), pp 256-263, 2016.
  23. Chen X#, Pan W#, Sui Y, Li H, Shi X, Guo X, Qi H, Xu C*, Liu W*. Acidic phospholipids govern the enhanced activation of IgG-B cell receptor. Nature Communications, 6(8552), 2015.
  24. Liu C#, Zhao X#, Xu L, Yi J, Shaheen S, Han W, Wang F, Zheng W, Xu C, Liu W. A negative-feedback function of PKCβ in the formation and accumulation of signaling-active B cell receptor microclusters within B cell immunological synapse. Journal of Leukocyte Biology, 97(5), pp 887-900, 2015.
  25. Wu W#, Yan C#, Shi X, Li L, Liu W, Xu C*. Lipid in T-cell receptor transmembrane signaling. Progress in Biophysics and Molecular Biology, 118(3), pp 130-138, 2015.
  26. Wang Y#, Gao J#, Guo X#, Tong T, Shi X, Li L, Qi M, Wang Y, Cai M, Jiang J, Xu C*, Ji H*, Wang H*. Regulation of EGFR nanocluster formation by ionic protein-lipid interaction. Cell Research, 24(8), pp 959-976, 2014.
  27. Li L#, Shi X#, Guo X, Li H, Xu C*. Ionic protein-lipid interaction at the plasma membrane: what can the charge do? Trends in Biochemical Sciences, 39(3), pp 130-140, 2014.
  28. Wertek F, Xu C*. Digital response in T cells: to be or not to be. Cell Research, 24(3), pp 265-266, 2014.
  29. Li P, Fu Z, Zhang Y, Zhang J, Xu C, Ma Y, Li B, Song B. The clathrin adaptor Numb regulates intestinal cholesterol absorption through dynamic interaction with NPC1L1. Nature Medicine, 20(1), pp 80-86, 2014.
  30. Shi X#, Bi Y#, Yang W#, Guo X, Jiang Y, Wan C, Li L, Bai Y, Guo J, Wang Y, Chen X, Wu B, Sun H, Liu W, Wang J*, Xu C*. Ca2+ regulates T-cell receptor activation by modulating the charge property of lipids. Nature, 493(7430), pp 111-115, 2013.
  31. Liu B#, Liu Y#, Du Y, Mardaryev A, Yang W, Chen H, Xu Z, Xu C, Zhang X, Botchkarev V, Zhang Y*, Xu G*. Cbx4 regulates the proliferation of thymic epithelial cells and thymus function. Development, 140(4), pp 780-788, 2013.
  32. Zhang K#, Pan Y#, Qi J, Yue J, Zhang M, Xu C, Li G*, Chen J*. Disruption of disulfide-restriction at integrin knees induces activation and ligand-independent signaling of α4β7. Journal of Cell Science, 126(Pt21), pp 5030-5041, 2013.
  33. Wang X#, Jimenez-Vargas J#, Xu C, Possani L*, Zhu S*. Positive selection-guided mutational analysis revealing two key functional sites of scorpion ERG K(+) channel toxins. Biochemical and Biophysical Research Communications, 429(1-2), pp 111-116, 2012.
  34. Gagnon E, Xu C, Yang W, Chu H, Call M, Chou J, Wucherpfennig K*. Response multilayered control of T cell receptor phosphorylation. Cell, 142(5), pp 669-671, 2010.
  35. Xu C#, Gagnon E#, Call M, Schnell J, Schwieters C, Carman C, Chou J*, Wucherpfennig K*. Regulation of T cell Receptor Activation by Dynamic Membrane Binding of the CD3e Cytoplasmic Tyrosine-Based Motif. Cell, 135(4), pp 702-713, 2008.
  36. Wang S, Huang L, Wicher D, Chi C*, Xu C*. Structure-function relationship of bifunctional scorpion toxin BmBKTx1. Acta Biochimica et Biophysica Sinica (Shanghai), 40(11), pp 955-963, 2008.
  37. O’Connor K#, McLaughlin KA#, De Jager P, Chitnis T, Bettelli E, Xu C, Robinson W, Cherry S, Bar-Or A, Banwell B, Fukaura H, Fukazawa T, Tenembaum S, Wong S, Tavakoli N, Idrissova Z, Viglietta V, Rostasy K, Pohl D, Dale R, Freedman M, Steinman L, Buckle G, Kuchroo V, Hafler D*, Wucherpfennig K*. Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein. Nature Medicine, 13(2), pp 211-217, 2007.
  38. Xu C, Call M, Wucherpfennig K. A membrane-proximal tetracysteine motif contributes to assembly of cd3de and cd3ge dimers with the T cell receptor. Journal of Biological Chemistry, 281(48), pp 36977-36984, 2006.
  39. Call M#, Schnell J#, Xu C, Lutz R, Chou J*, Wucherpfennig K*. The Structure of the ζζ Transmembrane Dimer Reveals Polar Features Essential for Dimerization and Assembly with the T cell Receptor. Cell, 127(2), pp 355-368, 2006.
  40. Jiang H, Xu C, Wang C, Fan C, Zhao T, Chen J, Chi C. Two novel O-superfamily conotoxins from Conus vexillum. Toxicon, 47(4), pp 425-436, 2006.
  41. Jiang H#, Wang C#, Xu C, Fan C, Dai X, Chen J, Chi C. A novel M-superfamily conotoxin with a unique motif from Conus vexillum. Peptides, 27(4), pp 682-689, 2006.
  42. Xu C#, Brône B#, Wicher D, Bozkurt O, Lu W, Huys I, Han Y, Tytgat J, Van Kerkhove E, Chi C. BmBKTx1, a novel Ca2+activated K+ channel blocker purified from the Asian scorpion Buthus martensi Karsch. Journal of Biological Chemistry, 279(33), pp 34562-34569, 2004.
  43. Xu C, He L, Brône B, Martin-Eauclaire M, Van Kerkhove E, Zhou Z, Chi C. A novel scorpion toxin blocking small conductance Ca2+ activated K+ channel. Toxicon, 43(8), pp 961-971, 2004.
  44. Cai Z#, Xu C#, Xu Y, Lu W, Chi C, Shi Y, Wu J. Solution structure of BmBKTx1, a new BKCa1 channel blocker from the Chinese scorpion Buthus martensi Karsch. Biochemistry, 43(13), pp 3764-3771, 2004.
  45. Huys I#, Xu C#, Wang C, Vacher H, Martin-Eauclaire M, Chi C, Tytgat J. BmTx3, a scorpion toxin with two putative functional faces separately active on A-type K+ and HERG currents. Biochemical Journal, 378(3), pp 45-52, 2004.
  46. Frénal K#, Xu C#, Wolff N, Wecker K, Gurrola G, Zhu S, Chi C, Possani L, Tytgat J*, Delepierre M*. Exploring structural features of the interaction between the scorpion toxinCnErg1 and ERG K+ channels. PROTEINS: Structure, Function, and Bioinformatics, 56(2), pp 367-375, 2004.
  47. Szyk A, Lu W, Xu C, Lubkowski J. Structure of the Scorpion Toxin BmBKTx1 Solved from Single Wavelength Anomalous Scattering of Sulfur. Journal of Structural Biology, 145(3), pp 289-294, 2004.
  48. Xu C, Zhu S, Chi C, Tytgat J. Turret and pore block of K+ channels: what is the difference? Trends in Pharmacological Sciences, 24(9), pp 446-448, 2003.

Education Background & Academic Experience
Nov. 2009- present, Principle Investigator, Institute of Biochemistry and Cell Biology, SIBS
Apr.-Sep. 2009, Instructor, Dana-Farber Cancer Institute, Harvard Medical School
Aug. 2004-Mar. 2009, Postdoctoral Fellow, Dana-Farber Cancer Institute, Harvard Medical School
Jul. 2004, Ph.D. Institute of Biochemistry and Cell Biology, SIBS

Research Team

 

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