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人才隊伍

許琛琦
研究員，研究組長，博士生導師，所長助理
E-mail: cqxu@@sibcb.ac.cn
實驗室主頁: xulab.sibcb.ac.cn

個人簡介：

　　許琛琦，研究員，1998年于華東師范大學獲得生物化學專業(yè)學士，2004年于中科院生化細胞所獲得生物化學與分子生物學博士學位，2004-2009年于哈佛大學Dana-Farber腫瘤研究所從事博士后研究，獲得Arthritis Foundation資助，后晉升為Instructor。2009年底加入中科院生化與細胞所，入選國家基金杰出青年基金。闡明了抗原免疫應答調(diào)控的新機制并發(fā)展了腫瘤免疫治療的新策略。工作已發(fā)表于Cell 2020, Nature 2018，Nature 2016，Nature 2013等，兩項成果入選中國科學十大進展/中國生命科學十大進展，其發(fā)明專利已成功進入轉(zhuǎn)化。榮獲上海市青年科技杰出貢獻獎(2020年)，中國青年科技獎(2018年)，中國生化與分子生物學會Promega生物化學獎(2018年)等榮譽。

社會任職：

研究方向：

淋巴細胞與疾病

研究工作：

　　免疫系統(tǒng)是機體執(zhí)行免疫應答及免疫功能的重要系統(tǒng)，它能夠區(qū)分“自身”和“非自身”，并通過清除“非自身物質(zhì)”來保護機體。免疫系統(tǒng)可以分為固有免疫和適應性免疫。固有免疫系統(tǒng)在低等動物中就開始出現(xiàn)，可以識別病原體所攜帶的特殊模式以及體內(nèi)的危險信號，從而迅速地做出免疫反應。適應性免疫系統(tǒng)是高等動物逐漸進化出的特殊功能系統(tǒng)，最大的特點是能夠針對不同的抗原做出高度特異性和靈敏性的免疫反應。T淋巴細胞(簡稱T細胞)是適應性免疫系統(tǒng)的主要功能細胞，在清除病原體和腫瘤細胞過程中發(fā)揮著至關(guān)重要的作用。T細胞的活性異常與腫瘤、自身免疫病等多種重大疾病直接相關(guān)?；赥細胞功能調(diào)控的腫瘤免疫治療已成為治療腫瘤的主要武器之一，在臨床上已取得了巨大的成功。但現(xiàn)有的基于信號轉(zhuǎn)導調(diào)控的腫瘤免疫治療手段只對部分病人有效，因此急需發(fā)展新的方法讓更多的病人受益。本研究組交叉利用免疫學、生物化學、生物物理學前沿手段，著力于T細胞活性調(diào)控的分子機制研究，揭示了T細胞發(fā)揮免疫功能的分子基礎，并且發(fā)展了新的腫瘤免疫治療方法。
　　1. 抗原免疫應答的調(diào)控機制
　　抗原免疫應答過程涉及多種免疫受體的協(xié)同作用。本課題組對抗原受體TCR，共刺激受體CD28和共抑制受體PD-1的活化機制做了深入而系統(tǒng)的研究，我們創(chuàng)新性地提出了“膜脂調(diào)控”理論，指出酸性磷脂可以通過靜電相互作用調(diào)控免疫受體的活化過程。
　　T細胞的活化主要依賴于抗原受體TCR(T-cell receptor)和共刺激受體CD28。我們的前期研究表明TCR的活性受酸性磷脂調(diào)控。帶負電的酸性磷脂可以和帶正電的TCR胞內(nèi)區(qū)動態(tài)結(jié)合，從而將TCR的磷酸化位點屏蔽在膜內(nèi)，保證TCR在靜息態(tài)T細胞中處于功能關(guān)閉狀態(tài)(Cell 2008)。我們隨后發(fā)現(xiàn)TCR初始信號引發(fā)的鈣離子內(nèi)流能夠反饋調(diào)控TCR。Ca2+可以直接結(jié)合酸性磷脂的磷酸根，中和其攜帶的負電荷，從而打破TCR與酸性磷脂之間的靜電相互作用，促進TCR功能位點的解屏蔽及磷酸化，從而放大TCR的活化信號(Nature 2013)。這一新的分子機制突破了以往對Ca2+功能的傳統(tǒng)認識。在這項工作基礎上，我們進一步發(fā)現(xiàn)Ca2+的正反饋調(diào)控還適用于CD28。酸性磷脂同樣可以屏蔽CD28的磷酸化位點，而Ca2+也能夠通過中和酸性磷脂負電荷的機制來放大CD28信號(Nature Structural & Molecular Biology 2017)。我們由此提出TCR，Ca2+，CD28這三者之間組成了一個雙環(huán)路的正反饋網(wǎng)絡，可以將微弱的初始抗原刺激信號迅速放大，使T細胞獲得完全的效應功能，從而為T細胞高靈敏性提供了信號基礎(圖1)?！澳ぶ{(diào)控”理論在我們的合作研究中同樣被證明適用于多種免疫受體，比如鈣離子在記憶型B細胞的迅速活化過程中也起到關(guān)鍵的作用(Nature Communications 2015，The Journal of Physical Chemistry Letters, 2017)。我們也撰寫了多篇綜述來闡述這個學術(shù)思想(Trends Biochem Sci 2014, Trends Immunol 2016, Nat Rev Immunol 2016)。
　　圖1. TCR-Ca2+-CD28雙環(huán)路正反饋模型。T細胞活化主要依賴TCR和CD28。這兩個關(guān)鍵受體的磷酸化位點都被酸性磷脂通過靜電效應屏蔽，而Ca2+可以通過中和酸性磷脂負電荷的形式釋放受體磷酸化位點，促進受體活化。TCR和CD28的活化都能夠誘導Ca2+內(nèi)流。TCR-Ca2+-CD28這三者之間由此形成雙環(huán)路的正反饋網(wǎng)絡，可以將微弱的初始刺激信號迅速放大，為T細胞的高抗原敏感性提供信號基礎。
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　　我們還發(fā)現(xiàn)TCR的結(jié)構(gòu)多態(tài)性和酪氨酸激酶Lck的底物選擇性是T細胞高特異性的分子基礎。通過單分子技術(shù)和液相核磁共振技術(shù)，我們發(fā)現(xiàn)TCR在不同的抗原刺激下會產(chǎn)生不一樣的開放性構(gòu)象，從而對Lck激酶有不同程度的招募;隨后Lck對TCR上的多個酪氨酸位點進行選擇性磷酸化，產(chǎn)生抗原特異性的磷酸化模式并引發(fā)不同的T細胞效應功能(圖2，Cell Research 2017，PNAS 2017)。
　　圖2. TCR結(jié)構(gòu)多態(tài)性模型。TCR可以在不同抗原刺激下產(chǎn)生不同的開放性構(gòu)象，從而引發(fā)特異性的下游信號通路，使得T細胞獲得不同的效應功能。這個模型解釋了T細胞獲得抗原特異性的信號基礎。
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　　我們同樣研究了T細胞的共抑制受體PD-1。T細胞在腫瘤微環(huán)境中會表現(xiàn)出功能耗竭的狀態(tài)，并伴隨著PD-1的異常高表達。目前在臨床上應用的PD-1或PD-L1抗體就是通過阻滯PD-1的抑制性信號，進而增強T細胞的抗腫瘤活性。我們發(fā)現(xiàn)了PD-1的降解機制及其在抗腫瘤過程中的重要性 (Nature 2018)?；罨疶細胞表面的PD-1會經(jīng)歷內(nèi)吞、泛素化和蛋白酶體的降解等一系列過程。我們找到了介導PD-1泛素化的E3連接酶FBXO38。在Fbxo38條件性敲除的小鼠體內(nèi)腫瘤生長的會更快，腫瘤浸潤T細胞的PD-1表達水平也更高。而PD-1抗體治療有效抑制了FBXO38缺失小鼠體內(nèi)腫瘤的生長，揭示了PD-1是FBXO38作用的直接靶點。FBXO38對PD-1表達量的調(diào)控為阻滯PD-1的抑制性信號提供了一個新的角度，也為針對PD-1的抗腫瘤藥物的研發(fā)提供新的思路。
　　2. 腫瘤免疫治療
　　近年來，本課題組利用自己在免疫受體和脂質(zhì)調(diào)控方面的基礎知識，提出了全新的腫瘤免疫治療理論及策略。一方面我們認為通過調(diào)控T細胞的代謝狀態(tài)可以讓其獲得更強的效應功能。我們發(fā)現(xiàn)膽固醇儲存通路的關(guān)鍵調(diào)節(jié)酶ACAT1是一個很好的調(diào)控靶點，抑制ACAT1的活性可以大大提高CD8+ T細胞(又名殺傷性T細胞)的抗腫瘤功能。其機理是ACAT1被抑制后，殺傷性T細胞膜上的游離膽固醇水平提高，從而讓TCR的聚集程度和信號轉(zhuǎn)導能力提高并使得T細胞的殺傷性免疫突觸形成更加有效。我們進一步利用ACAT1的小分子抑制劑Avasimibe在動物模型中治療多種腫瘤，發(fā)現(xiàn)該抑制劑具有很好的抗腫瘤效應;并且Avasimibe與現(xiàn)有的腫瘤免疫治療臨床藥物anti-PD-1聯(lián)用后效果更佳。Avasimibe曾經(jīng)作為心血管疾病的藥物進行過三期臨床試驗，雖然這個小分子抑制劑對動脈粥樣硬化沒有明顯的治療效果，但是它具有很好的人體安全性，因此Avasimibe具有很好的潛力被開發(fā)成抗腫瘤藥物(Nature 2016，中國生命科學十大進展)。
- 　　圖3. 基于膽固醇代謝調(diào)控的腫瘤免疫治療新方法。膽固醇酯化酶ACAT1可以將細胞內(nèi)的游離膽固醇轉(zhuǎn)化為膽固醇酯。抑制CD8+ T細胞的ACAT1活性可以使細胞質(zhì)膜的游離膽固醇水平上升，從而使得TCR信號增強并讓殺傷性免疫突觸更成熟。T細胞腫瘤抗原免疫應答由此變得更加高效。
　　
　　另一方面我們基于CD3e 蛋白的多重信號功能發(fā)展了一種新的CAR-T細胞治療技術(shù)，可以提高細胞的抗腫瘤功能并降低細胞因子風暴的風險。通過建立絕對定量質(zhì)譜系統(tǒng)，我們對CD3分子內(nèi)的所有酪氨酸位點定量并發(fā)現(xiàn)CD3e ITAM呈現(xiàn)出獨特的單磷酸化的模式。進一步的研究發(fā)現(xiàn)，CD3e ITAM可以特異性的招募抑制性激酶Csk來抑制Lck介導的磷酸化過程，表明天然的抗原受體TCR同時具有活化元件(CD3z)和調(diào)控元件(CD3e)，具有信號自我調(diào)控的能力。目前臨床上使用的CAR-T細胞，其人工合成的抗原受體CAR卻只利用了CD3z。當我們將CD3e加入至臨床上使用的CAR中后，CAR-T細胞的抗腫瘤能力得到了增強。從機制的角度來看，CD3e中的ITAM基序可以招募Csk來下調(diào)CAR-T細胞的細胞因子的分泌水平，BRS基序可以招募p85進而增強CAR-T細胞的生長持續(xù)性。因此在CAR中加入了CD3e可以引入更豐富的信號調(diào)控機制，從而提升CAR-T的整體表現(xiàn)，為未來的CAR-T細胞治療提供新的發(fā)展方向(Cell 2020，中國生命科學十大進展)。
　　圖4. 基于CD3e 蛋白多重信號功能而設計的新型CAR-T細胞療法。TCR的CD3e 鏈具有特殊的信號轉(zhuǎn)導功能，可以同時招募抑制性分子Csk和活化性分子PI3K。將CD3e 胞內(nèi)區(qū)加入臨床使用的CAR序列中，可使得CAR-T細胞生長持續(xù)性更好，抗腫瘤功能更強，并且細胞因子釋放綜合癥的風險降低。
　　綜上所述，本研究組在T細胞的基礎研究中發(fā)現(xiàn)了T細胞活化的新分子機制，同時在免疫受體信號和代謝調(diào)控兩個角度發(fā)展了新的腫瘤免疫治療方法。今后我們將主要研究在不同生理和病理環(huán)境下的T細胞脂代謝特征，并且尋找新的“代謝檢查點”用于代謝調(diào)控，同時進行CAR-T細胞的功能機制研究，為未來CAR-T細胞的設計與臨床應用提供新的思路與發(fā)展方向。?

承擔科研項目情況：

代表論著：

(*通訊作者，#第一作者)
1. Jiang Y^#, Dai A^#, Huang Y^#, Li H^#, Cui J^#, Yang H, Si L, Jiao T, Ren Z, Zhang Z, Mou S, Zhu H, Guo W, Huang Q, Li Y, Xue M, Jiang J, Wang F, Li L, Zhong Q, Wang K, Liu B, Wang J, Fan G, Guo J, Chen L, Workman CJ, Shen Z^*, Kong Y^*, Vignali DAA^*,?Xu C^*, Wang H^*. Ligand-induced ubiquitination unleashes LAG3 immune checkpoint function by hindering membrane sequestration of signaling motifs.?Cell, 188(9):2354-2371.e18, 2025.
2. Xu XY^#, Chen H^#, Ren Z^#, Xu XM^#, Wu W, Yang H, Wang J, Zhang Y, Zhou Q, Li H, Zhang S, Wang H*,?Xu C*. Phase separation of chimeric antigen receptor promotes immunological synapse maturation and persistent cytotoxicity.?Immunity,?57(12): 2755-2771, 2024.
3. Shi X, He X, Xu C. Charge-based immunoreceptor signalling in health and disease.?Nature Reviews Immunology,?25(4):298-311, 2024.
4. Ren Z^#, Wang K^#, Zhang Y^#, Chen H, Zhu Y, Li H, Lou J^*, Wang H^*,?Xu C^*.?Transient hydroxycholesterol treatment restrains TCR signaling to promote long-term immunity.?Cell Chemical Biology, 31(5):920-931.e6, 2024.
5. Shi Y, Zheng X, Peng H,?Xu C, Sun R, Tian Z^*, Sun H^*, Wang X^*. The E3 Ubiquitin Ligase FBXO38 Maintains the Antitumor Function of Natural Killer Cells by Sustaining IL15R Signaling.?Cancer Immunology Research?12(10):1438-1451,2024.
6. Bai Y^#, Li T^#, Wang Q^#, You W^#,?Yang H,?Xu X, Li Z, Zhang Y, Yan C, Yang L, Qiu J, Liu Y, Chen S,?Wang D,?Huang B, Liu K, Song B, Wang Z, Li K, Liu X, Wang G, Yang W, Chen J, Hao P, Zhang Z, Wang Z^*, Zhu Z^*,?Xu C^*,?Shaping immune landscape of colorectal cancer by cholesterol metabolites,?EMBO Molecular Medicine?16(2):334-360, 2024.
7. Chen H^#, Xu X^#, Hu W^#, Wu S, Xiao J, Wu P, Wang X, Han X, Zhang YR Zhang Y, Jiang N, Liu W, Lou C, Chen W^*, Xu C^*, Lou J^*, Self-programmed dynamics of T cell receptor condensation, Proceedings of the National Academy of Sciences of the United States of America, 120(28):e2217301120, 2023.
8. Wang H^#*, Huang Y^#, Xu C^*, Charging CAR by Electrostatic Power, Immunological reviews, doi: 10.1111/imr.13232, 2023.
9. Yan C^#, Zheng L^#, Jiang S^#, Yang H^#, Guo J^#, Jiang L, Li T, Zhang H, Bai Y, Lou Y, Zhang Q, Liang T, Schamel W, Wang H, Yang W, Zhu Z, Song B^*, Xu C^*. Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity. Cancer Cell, S1535-6108(23)00142-3, 2023.
10. Mo?s B, Li H, Molina-Ortiz P, Radermecker C, Rosu A, Catsyne C , Sayyed S, Fontela J, Duque M, Mostafa A, Azzi A, Barata J, Merino R, Xu C, Desmet C, Schurmans S. INPP5K controls the dynamic structure and signaling of wild type and mutated, leukemia-associated IL7 receptors. Blood, 141(14):1708-1717, 2023.
11. Wang X^#,?He X^#,?Jiang S^#,?Fu Z^#,?Jiang S,?Zhao X,?Zhao C,?Li Y,?Li D,?Zhang W,?Ai J^*,?Zhang Y^*,?Xu C^*,?Wang P^*. Limited enhancement of antibody and B-cell responses to prototype booster vaccination following SARS-CoV-2 Delta breakthrough infection. Journal of Medical Virology, 95(2):e28540, 2023.
12. Chen J^#, Qiu S^#, Li W^#, Wang K, Zhang Y, Yang H, Liu B, Li G, Li L, Chen M, Lan J, Niu J, He P, Cheng L, Fan G, Liu X, Song X^*, Xu C^*, Wu H^*, Wang H^*. Tuning Charge Density of Chimeric Antigen Receptor Optimizes CAR-T Cell Fitness. Cell Research, 33(5):341-354, 2023.
13. Ai J^#, Guo J^#, Zhang H^#, Zhang Y^#, Yang H^#, Lin K^#, Song J^#, Fu Z^#, Fan M^#, Zhang Q, Wang H, Zhao Y, He Z, Cui A, Zhou Y, Wu J, Zhou M, Yuan G, Kang B, Zhao N, Xu Y, Zhu M, Wang Y, Zhang Z, Jiang N^*, Qiu C^*, Xu C^*, Zhang W^*, Cellular basis of enhanced humoral immunity to SARS-CoV-2 upon homologous or heterologous booster vaccination analyzed by single-cell immune profiling, Cell Discovery, 8(1):114, 2022.
14. Wang X^#, Ai J^#, Li X^#, Zhao X^#, Wu J^#, Zhang H^#, He X^#, Zhao C, Qiao R, Li M, Cui Y, Hu Z^*, Xu C^*, Zhang W^* and Wang P^*, Neutralization of Omicron BA.4/BA.5 and BA.2.75 by booster vaccination or BA.2 breakthrough infection sera, Cell Discovery, 8(1):110, 2022.
15. Wang Q, Zhu T, Miao N, Qu Y, Wang Z, Chao Y, Wang J, Wu W, Xu X, Xu C, Xia L, Wang F, Disulfiram bolsters T-cell anti-tumor immunity through direct activation of LCK-mediated TCR signaling, The EMBO Journal, 41(16):e110636, 2022
16. Pathan-Chhatbar S?, Drechsler C, K,Morath? A, Wu W, OuYang B, Xu C, Schamel? W*, Direct Regulation of the T Cell Antigen Receptor's Activity by Cholesterol. Frontiers in Cell and Developmental Biology, 8:615996, 2021
17. Wen M#*, Cao Y#, Wu B#, Xiao T, Cao R, Wang Q, Liu X, Xue H, Yu Y, Lin J,?Xu C, Xu J, OuYang B*,?PD-L1 degradation is regulated by electrostatic membrane association of its cytoplasmic domain.?Naturer Communications,?12(1):5106, 2021.
18. Xu Y, Ma J, Luo H, Shi Y, Liu H, Sun A,?Xu C, Ji H, Liu X,?Chromatin assembly factor 1B critically controls the early development but not function acquisition of invariant natural killer T cells in mice.?Eur J Immunol. 51(7):1698-1714, 2021
19. Wang H*, Song X, Shen L, Wang X, Xu C*,?Exploiting T cell signaling to optimize engineered T cell therapies,?Trends?in?Cancer, S2405-8033(21)00224-7, 2021.
20. Li T#, Cai H#, Zhao Y#, Li Y#, Lai Y#, Yao H#, Liu L# , Sun Z#, Vlissingen M, Kuiken T, GeurtsvanKessel C , Zhang N , Zhou B , Lu L , Gong Y, Qin W , MondalM , Duan B , Xu S , Richard A, Raoul H , Chen J, Xu C, Wu L , Zhou H , Huang Z , Zhang X , Li J , Wang Y , Bi Y , Rockx B , Chen J*, Meng F*, Lavillette D*, Li D*, Uncovering a conserved vulnerability site in SARS-CoV-2 by a human antibody，EMBO Molecular Medicine ,13(12):e14544, 2021
21. Delgoffe G, Xu C, Mackall C, Green M, Gottschalk S, Speiser D, Zehn D, Beavis P, The role of exhaustion in CAR T cell therapy. Cancer Cell, 39: 888, 2021.
22. Wu W^#, Zhou Q^#, Masubuchi T^#, Shi X^#, Li H, Xu X, Huang M, Meng L, He X, Zhu H, Gao S, Zhang N, Jing R, Sun J, Wang H, Hui E*, Wong C^*, Xu C^*, Multiple signaling roles of CD3e and its application in CAR-T cell therapy. Cell, 182(4): 855-871.e23, .2020.
23. Li W^#, Qiu S^#, Jian C^#, Jiang S, Chen W, Jiang J, Wang F, Si W, Shu Y, Wei P, Fan G, Tian R, Wu H^*, Xu C^*, Wang H^*, Chimeric Antigen Receptor Designed to Prevent Ubiquitination and Downregulation Showed Durable Antitumor Efficacy. Immunity, 53(2):456-470.e6. 2020.
24. He X, Xu C^*, Immune checkpoint signaling and cancer immunotherapy. Cell Research, 30(8): 660-669, 2020.
25. Guo J, Xu C^*, Screening for the next-generation T cell therapies. Cancer Cell, 37(5): 627-629, 2020.
26. 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.
27. He X, Xu C^*, PD-1: A Driver or Passenger of T Cell Exhaustion? Molecular Cell, 77(5): 930-931, 2020.
28. Huang B, Song B, Xu C^*. Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities. Nature Metabolism, 2: 132-141, 2020.
29. Xu X^#, Li H^#, Xu, C^*. Structural understanding of T cell receptor triggering. Cellular & Molecular Immunology, 17(3): 193-202, 2020.
30. Xu C^*, Li HB^*, Flavell RA^*, A special collection of reviews on frontiers in immunology. Cell Research, 30(10):827-828, 2020.
31. Sun A^#, Xu K^#, Liu H, Li H, Shi Y, Zhu X, Liang T, Li X, Cao X, Ji Y, Jiang T, Xu C, Liu X^*, The evolution of zebrafish RAG2 protein is required for adapting to the elevated body temperature of the higher endothermic vertebrates. Scientific reports, 10(1):4126, 2020.
32. 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.
33. 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.
34. 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.
35. 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.
36. 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.
37. 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.
38. 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.
39. Bietz A^#, Zhu H^#, Xue M, Xu C^*. Cholesterol Metabolism in T Cells. Frontiers in Immunology, 8:1664, 2017.
40. 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 and Molecular Biology, 24 (12): 1081-1092, 2017.
41. 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. Journal of Physical Chemistry Letters, 8(16): 3765-3769, 2017.
42. 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. Proc Natl Acad Sci U S A, 114(29): E5891-E5899, 2017.
43. 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): 505-525, 2017.
44. 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 antitumour response of CD8⁺ T cells by modulating cholesterol metabolism. Nature, 531 (7596): 651-655, 2016.
45. Wu W, Shi X, Xu C^*. Regulation of T cell signalling by membrane lipids. Nature Reviews Immunology, 16 (11): 690-701, 2016.
46. 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 YH, 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. Journal of Experimental Medicine. 213 (12): 2707-2727, 2016.
47. Liu W^*, Wang H, Xu C^*. Antigen Receptor Nanoclusters: Small Units with Big Functions. Trends in Immunology. 37 (10): 680-689, 2016.
48. 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): 256-263, 2016.
49. 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.
50. 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): 887-900, 2015
51. 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): 130-138, 2015.
52. 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): 959-976, 2014.
53. 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): 130-140, 2014.
54. Wertek F, Xu C^*. Digital response in T cells: to be or not to be. Cell Research, 24(3): 265-266, 2014.
55. 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): 80-86, 2014.
56. 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): 111-115, 2013.
57. 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): 780-788, 2013.
58. 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): 5030-5041, 2013.
59. 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): 111-116, 2012.
60. 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): 669-671, 2010.
61. 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): 702-713, 2008.
62. 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): 955-963, 2008.
63. 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): 211-217, 2007.
64. 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): 36977-36984, 2006.
65. 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): 355-368, 2006.
66. 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): 425-436, 2006.
67. 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): 682-689, 2006.
68. Xu C^#, Br？ne 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): 34562-34569, 2004.
69. Xu C, He L, Br？ne 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): 961-971, 2004.
70. 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): 3764-3771, 2004.
71. 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): 45-52, 2004.
72. 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): 367-375, 2004.
73. 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): 289-294, 2004.
74. 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): 446-448, 2003.

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