切换至 "中华医学电子期刊资源库"

中华肾病研究电子杂志 ›› 2026, Vol. 15 ›› Issue (01) : 29 -33. doi: 10.3877/cma.j.issn.2095-3216.2026.01.005

综述

剪切型X-盒结合蛋白1在自身免疫性疾病中的作用研究进展
潘美京1, 许国双2,()   
  1. 1710021 西安医学院
    2710032 西安,空军军医大学第一附属医院(西京医院)
  • 收稿日期:2025-02-28 出版日期:2026-02-28
  • 通信作者: 许国双
  • 基金资助:
    陕西省重点产业链社发公关课题(2022ZDLSF03-12)

Progress in the study of the role of spliced X-box-binding protein 1 in autoimmune diseases

Meijing Pan1, Guoshuang Xu2,()   

  1. 1Xi′an Medical University, Xi′an 710021
    2First Affiliated Hospital of Air Force Medical University (Xijing Hospital), Xi′an 710032; Shaanxi Province, China
  • Received:2025-02-28 Published:2026-02-28
  • Corresponding author: Guoshuang Xu
引用本文:

潘美京, 许国双. 剪切型X-盒结合蛋白1在自身免疫性疾病中的作用研究进展[J/OL]. 中华肾病研究电子杂志, 2026, 15(01): 29-33.

Meijing Pan, Guoshuang Xu. Progress in the study of the role of spliced X-box-binding protein 1 in autoimmune diseases[J/OL]. Chinese Journal of Kidney Disease Investigation(Electronic Edition), 2026, 15(01): 29-33.

剪切型X-盒结合蛋白1(spliced X-box-binding protein 1,XBP1s)作为内质网应激信号通路中的核心转录因子,能够调控蛋白质折叠与降解,影响B细胞、T细胞和树突状细胞等免疫细胞功能,在炎症反应和免疫介导性疾病中起关键作用,成为治疗自身免疫性疾病的潜在靶点。针对XBP1s的靶向小分子药物、RNA干扰技术等治疗策略正在开发中。本文主要综述XBP1s在自身免疫性疾病中的重要作用及其分子机制,并讨论靶向干预XBP1s精准治疗自身免疫性疾病的应用前景。

Spliced X-box-binding protein 1 (XBP1s), a core transcription factor in the endoplasmic reticulum stress signaling pathway, regulates protein folding and degradation, influences the functions of immune cells such as B cells, T cells, and dendritic cells, and plays a key role in inflammatory responses and immune-mediated diseases. As such, it has emerged as a potential therapeutic target for autoimmune disorders. Targeted therapeutic strategies against XBP1s, including small-molecule drugs and RNA interference technologies, are currently under development. Targeted therapeutic strategies against XBP1s, including small-molecule drugs and RNA interference technologies, are currently under development. This review summarized the pivotal roles and molecular mechanisms of XBP1s in autoimmune diseases and discussed the application prospect of targeted intervention of XBP1s in the precision therapy of autoimmune diseases.

图1 剪切型X-盒结合蛋白1介导的未折叠蛋白反应在类风湿性关节炎滑膜细胞炎症中的作用机制注:XBP1s:spliced X-box-binding protein 1,剪切型X-盒结合蛋白1;IRE1α:inositol-requiring enzyme 1,肌醇依赖酶1α;TNF-α:tumour necrosis factor-α,肿瘤坏死因子-α;IL-6:interleukin-6,白细胞介素-6;IL-1β:interleukin-1β,白细胞介素-1β;MMPs:matrix metalloproteinases,基质金属蛋白酶;VEGF:vascular endothelial growth factor,血管内皮生长因子;NF-κB:nuclear factor-κB,核因子κB;IκB:inhibitor of NF-κB,核因子κB抑制蛋白;JNK:c-Jun N-terminal kinase,c-Jun氨基末端激酶;STAT3:signal transducer and activator of transcription 3,信号转导与转录激活因子3;在类风湿性关节炎病理环境下,滑膜细胞内质网发生应激,内质网应激传感器肌醇依赖酶1α被激活,介导XBP1的信使RNA非常规剪接,生成有活性的剪接形式XBP1s入核,通过TNF-α与STAT3作为转录因子调控下游靶基因TNF-α、IL-6、IL-1β、MMPs和VEGF等关键炎症因子和降解酶的表达与释放;上述因子进一步激活NF-κB、JNK和STAT3等促炎信号,最终导致滑膜组织慢性炎症、增生及关节软骨与骨破坏
[1]
Dumas G, Arabi YM, Bartz R, et al. Diagnosis and management of autoimmune diseases in the ICU [J]. Intensive Care Med, 2024, 50(1):17-35.
[2]
Merighi A, Lossi L. Endoplasmic reticulum stress signaling and neuronal cell death [J]. Int J Mol Sci, 2022, 23(23): 15186.
[3]
Sano R, Reed JC. ER stress-induced cell death mechanisms [J]. Biochim Biophys Acta, 2013, 1833(12): 3460-3470.
[4]
Szegezdi E, Logue SE, Gorman AM, et al. Mediators of endoplasmic reticulum stress-induced apoptosis [J]. EMBO Rep, 2006, 7(9): 880-885.
[5]
Tabas I, Ron D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress [J]. Nat Cell Biol, 2011, 13(3): 184-190.
[6]
Chen S, Chen J, Hua X, et al. The emerging role of XBP1 in cancer [J]. Biomed Pharmacother, 2020, 127: 110069.
[7]
Garg AD, Kaczmarek A, Krysko O, et al. ER stress-induced inflammation: Does it aid or impede disease progression? [J]. Trends Mol Med, 2012, 18(10): 589-598.
[8]
Xu G, Liu K, Anderson J, et al. Expression of XBP1s in bone marrow stromal cells is critical for myeloma cell growth and osteoclast formation [J]. Blood, 2012, 119(18): 4205-4214.
[9]
Bettigole SE, Glimcher LH. Endoplasmic reticulum stress in immunity [J]. Annu Rev Immunol, 2015, 33(1): 107-138.
[10]
So JS. Roles of endoplasmic reticulum stress in immune responses [J]. Mol Cells, 2018, 41(8): 705-716.
[11]
Iwakoshi NN, Lee AH, Vallabhajosyula P, et al. Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1 [J]. Nat Immunol, 2003, 4(4): 321-329.
[12]
Park SM, Kang TI, So JS. Roles of XBP1s in transcriptional regulation of target genes [J]. Biomedicines, 2021, 9(7): 791.
[13]
Gass JN, Gifford NM, Brewer JW. Activation of an unfolded protein response during differentiation of antibody-secreting B cells [J]. J Biol Chem, 2002, 277(50): 49047-49054.
[14]
Brucklacher-Waldert V, Ferreira C, Stebegg M, et al. Cellular stress in the context of an inflammatory environment supports TGF-β-independent T helper-17 differentiation [J]. Cell Rep, 2017, 19(11): 2357-2370.
[15]
Stadhouders R, Lubberts E, Hendriks RW. A cellular and molecular view of T helper 17 cell plasticity in autoimmunity [J]. J Autoimmun, 2018, 87: 1-15.
[16]
Pramanik J, Chen X, Kar G, et al. Genome-wide analyses reveal the IRE1a-XBP1 pathway promotes T helper cell differentiation by resolving secretory stress and accelerating proliferation [J]. Genome Med, 2018, 10(1): 76.
[17]
Xiao D, Li S, Gui B, et al. Effect of uremic serum on Th17/Treg cell balance and endoplasmic reticulum stress in rats [J]. Biomed Pharmacother, 2020, 131: 110705.
[18]
Ang Z, Er JZ, Ding JL. The short-chain fatty acid receptor GPR43 is transcriptionally regulated by XBP1 in human monocytes [J]. Sci Rep, 2015, 5(1): 8134.
[19]
Martinon F, Chen X, Lee AH, et al. TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages [J]. Nat Immunol, 2010, 11(5): 411-418.
[20]
Bettigole SE, Lis R, Adoro S, et al. The transcription factor XBP1 is selectively required for eosinophil differentiation [J]. Nat Immunol, 2015, 16(8): 829-837.
[21]
Iwakoshi NN, Pypaert M, Glimcher LH. The transcription factor XBP-1 is essential for the development and survival of dendritic cells [J]. J Exp Med, 2007, 204(10): 2267-2275.
[22]
Hu F, Yu X, Wang H, et al. ER stress and its regulator X-box-binding protein-1 enhance polyIC-induced innate immune response in dendritic cells [J]. Eur J Immunol, 2011, 41(4): 1086-1097.
[23]
Cubillos-Ruiz JR, Silberman PC, Rutkowski MR, et al. ER stress sensor XBP1 controls anti-tumor immunity by disrupting dendritic cell homeostasis [J]. Cell, 2015, 161(7): 1527-1538.
[24]
Lipsky PE. Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity [J]. Nat Immunol, 2001, 2(9): 764-766.
[25]
Iwata S, Tanaka Y. B-cell subsets, signaling and their roles in secretion of autoantibodies [J]. Lupus, 2016, 25(8): 850-856.
[26]
Xiang L, Liu A, Xu G. Expression of XBP1s in B lymphocytes is critical for pristane-induced lupus nephritis in mice [J]. Am J Physiol Renal Physiol, 2020, 318(5): F1258-F1270.
[27]
Yap D, Lai K. Pathogenesis of renal disease in systemic lupus erythematosus--the role of autoantibodies and lymphocytes subset abnormalities [J]. Int J Mol Sci, 2015, 16(4): 7917-7931.
[28]
Yap DYH, Chan TM. B cell abnormalities in systemic lupus erythematosus and lupus nephritis-role in pathogenesis and effect of immunosuppressive treatments [J]. Int J Mol Sci, 2019, 20(24): 6231.
[29]
De Luca F, Shoenfeld Y. The microbiome in autoimmune diseases [J]. Clin Exp Immunol, 2019, 195(1): 74-85.
[30]
Navid F, Colbert RA. Causes and consequences of endoplasmic reticulum stress in rheumatic disease [J]. Nat Rev Rheumatol, 2016, 13(1): 25-40.
[31]
Savic S, Ouboussad L, Dickie LJ, et al. TLR dependent XBP-1 activation induces an autocrine loop in rheumatoid arthritis synoviocytes [J]. J Autoimmun, 2014, 50(100): 59-66.
[32]
Corrigall VM, Bodman-Smith MD, Brunst M, et al. Inhibition of antigen-presenting cell function and stimulation of human peripheral blood mononuclear cells to express an antiinflammatory cytokine profile by the stress protein BiP: relevance to the treatment of inflammatory arthritis [J]. Arthritis Rheum, 2004, 50(4): 1164-1171.
[33]
Hu F, Tang Y, Wang P, et al. Endoplasmic reticulum stress perpetuated Toll-like receptor signalling-mediated inflammation in rheumatoid arthritis via X-box-binding protein-1 [J]. Clin Exp Rheumatol, 2021, 39(4): 859-867.
[34]
Piperi C, Adamopoulos C, Papavassiliou AG. XBP1: a pivotal transcriptional regulator of glucose and lipid metabolism [J]. Trends Endocrinol Metab, 2016, 27(3): 119-122.
[35]
Volkmann K, Lucas JL, Vuga D, et al. Potent and selective inhibitors of the inositol-requiring enzyme 1 endoribonuclease [J]. J Biol Chem, 2011, 286(14): 12743-12755.
[36]
Cross BCS, Bond PJ, Sadowski PG, et al. The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule [J]. Proc Natl Acad Sci, 2012, 109(15): E869-E878.
[37]
Mimura N, Fulciniti M, Gorgun G, et al. Blockade of XBP1 splicing by inhibition of IRE1α is a promising therapeutic option in multiple myeloma [J]. Blood, 2012, 119(24): 5772-5781.
[38]
Papandreou I, Denko NC, Olson M, et al. Identification of an IRE1α endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma [J]. Blood, 2011, 117(4): 1311-1314.
[39]
Ri M, Tashiro E, Oikawa D, et al. Identification of toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing [J]. Blood Cancer J, 2012, 2(7): e79.
[40]
Sanches M, Duffy NM, Talukdar M, et al. Structure and mechanism of action of the hydroxy-aryl-aldehyde class of IRE1 endoribonuclease inhibitors [J]. Nat Commun, 2014, 5(1): 4202.
[41]
Wang L, Perera BGK, Hari SB, et al. Divergent allosteric control of the IRE1α endoribonuclease using kinase inhibitors [J]. Nat Chem Biol, 2012, 8(12): 982-989.
[42]
Ji L, Hou X, Deng X, et al. Jieduquyuziyin prescription-treated rat serum suppresses activation of peritoneal macrophages in MRL/lpr lupus mice by inhibiting IRAK1 signaling pathway [J]. Evid Based Complement Alternat Med, 2019, 2019: 2357217.
[43]
Wiseman RL, Zhang Y, Lee KPK, et al. Flavonol activation defines an unanticipated ligand-binding site in the kinase-RNase domain of IRE1 [J]. Mol Cell, 2010, 38(2): 291-304.
[44]
Zhou Z, Li A, Wang Z, et al. Blimp-1 siRNA inhibits B cell differentiation and prevents the development of lupus in mice [J]. Hum Immunol, 2013, 74(3): 297-301.
[45]
Chen X, Iliopoulos D, Zhang Q, et al. XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway [J]. Nature, 2014, 508(7494): 103-107.
[46]
Leung-Hagesteijn C, Erdmann N, Cheung G, et al. XBP1s-negative tumor B cells and pre-plasmablasts mediate therapeutic proteasome inhibitor resistance in multiple myeloma [J]. Cancer Cell, 2013, 24(3): 289-304.
[47]
Mei Y, Wang X. RNA modification in mRNA cancer vaccines [J]. Clin Exp Med, 2023, 23(6): 1917-1931.
[1] 朱锦江, 徐杰丰, 葛风, 曹光立, 王旭光, 周梅亚, 陈铁江, 张茂. hESC-MSCs改善猪心肺复苏后心功能障碍的作用及机制研究[J/OL]. 中华危重症医学杂志(电子版), 2025, 18(05): 353-361.
[2] 孙鸿坤, 艾虹, 陈正. 内质网应激介导的牙周炎骨改建失衡的研究进展[J/OL]. 中华口腔医学研究杂志(电子版), 2024, 18(04): 211-218.
[3] 李杰, 冉永红, 郝玉徽. miR-21 靶向环腺苷酸应答元件结合蛋白样蛋白2 加重放射性肺纤维化的作用机制[J/OL]. 中华肺部疾病杂志(电子版), 2025, 18(02): 220-225.
[4] 许娟, 张党锋. 尼达尼布对肺纤维化小鼠肺功能及内质网应激反应的影响[J/OL]. 中华肺部疾病杂志(电子版), 2023, 16(05): 673-675.
[5] 张广权, 洪生杰, 陈显育, 王继才, 翟航, 吴芬芳, 史宪杰. 生物信息学分析内质网应激相关基因在非酒精性脂肪性肝炎发病中的作用[J/OL]. 中华肝脏外科手术学电子杂志, 2025, 14(05): 761-769.
[6] 朱蓉蓉, 王俭勤. 通过调控内质网应激信号通路治疗糖尿病肾病的研究进展[J/OL]. 中华肾病研究电子杂志, 2025, 14(02): 104-109.
[7] 桑田, 赵磊, 佟琰, 欧阳清, 陈香美. 急性肾损伤的内质网应激相关基因和通路的生物信息学分析[J/OL]. 中华肾病研究电子杂志, 2024, 13(01): 26-33.
[8] 孔维萍, 张刘波, 刘坚, 张卓莉, 于峰, 刘玉宁, 吴庆军, 王金平, 杨悦, 陶庆文, 谢院生. 系统性红斑狼疮及其主要脏器损害的中西医结合诊治[J/OL]. 中华肾病研究电子杂志, 2024, 13(01): 9-15.
[9] 杨以太, 王淑莹, 陈月阳, 王景景, 李泽萌, 任党利, 孙洪涛. 莪术醇通过调控eif2a/CHOP信号通路介导的细胞凋亡抑制创伤后应激障碍[J/OL]. 中华神经创伤外科电子杂志, 2025, 11(02): 103-110.
[10] 卞修蒙, 吴凯, 庞亮, 王鹏, 郑龙坡. 2009年至2023年美国成年人类风湿性关节炎与中风之间的关联:NHANES的一项横断面研究[J/OL]. 中华老年骨科与康复电子杂志, 2025, 11(05): 287-294.
[11] 徐弢, 张丽蓉, 连红强. PERK在神经退行性变性疾病中作用机制的研究进展[J/OL]. 中华脑科疾病与康复杂志(电子版), 2025, 15(05): 298-302.
[12] 戴婧, 林敏, 胡迎春. 内镜黏膜下剥离术治疗以黏膜下隆起为表现的IgG4相关性胃病一例[J/OL]. 中华消化病与影像杂志(电子版), 2025, 15(06): 676-680.
[13] 樊勇, 郝燕捷, 赵娟, 耿研, 张卓莉. 免疫检查点抑制剂治疗既往存在自身免疫性疾病的肿瘤患者:挑战与期待[J/OL]. 中华临床医师杂志(电子版), 2024, 18(12): 1146-1149.
[14] 高君伟, 刘皋林. 自身免疫性疾病的药物治疗[J/OL]. 中华临床医师杂志(电子版), 2023, 17(12): 1209-1211.
[15] 孟丽君, 宋芹, 邵莉, 李健. 系统性红斑狼疮合并肺动脉高压患者外周血T淋巴细胞亚群水平变化及临床意义[J/OL]. 中华诊断学电子杂志, 2024, 12(01): 38-43.
阅读次数
全文


摘要


AI


AI小编
你好!我是《中华医学电子期刊资源库》AI小编,有什么可以帮您的吗?