CD40

CD40
已知的結構
PDB	直系同源搜索: PDBe RCSB
PDBID列表
	1CZZ、1D00、1FLL、1LB6、3QD6、5DMJ、5IHL、5DMI
識別號
别名	CD40；, Bp50, CDW40, TNFRSF5, p50, CD40 (protein), CD40 molecule
外部ID	OMIM：109535 MGI：88336 HomoloGene：954 GeneCards：CD40
相關疾病
	類風濕性關節炎、第三型高IgM症候群
基因位置（人类）
染色体	20號染色體
终止	46,129,863 bp
基因位置（小鼠）
染色体	小鼠2号染色体
终止	164,914,868 bp
RNA表达模式
	; ; ; ;
	查阅更多表达数据
基因本體
分子功能	• antigen binding; • signal transducer activity; • 血浆蛋白结合; • tumor necrosis factor-activated receptor activity; • 酶结合; • 泛素蛋白连接酶结合; • protein domain specific binding; • signaling receptor activity;
細胞組分	• 細胞質; • integral component of membrane; • 細胞內膜結合細胞器; • 膜; • 细胞膜; • integral component of plasma membrane; • 細胞外區域; • cell surface; • CD40 receptor complex; • 外排體; • external side of plasma membrane; • 細胞外空間; • soma; • varicosity;
生物學過程	• positive regulation of protein phosphorylation; • positive regulation of MAP kinase activity; • positive regulation of interleukin-12 production; • Akt/PKB信号通路; • positive regulation of protein kinase C signaling; • immune system process; • cellular calcium ion homeostasis; • tumor necrosis factor-mediated signaling pathway; • immune response-regulating cell surface receptor signaling pathway; • platelet activation; • multicellular organism development; • B cell activation; • positive regulation of GTPase activity; • response to lipopolysaccharide; • B cell proliferation; • cellular response to mechanical stimulus; • positive regulation of endothelial cell apoptotic process; • regulation of cell population proliferation; • positive regulation of B cell proliferation; • positive regulation of NF-kappaB transcription factor activity; • defense response to virus; • 免疫反应; • regulation of immune response; • positive regulation of I-kappaB kinase/NF-kappaB signaling; • apoptotic signaling pathway; • positive regulation of isotype switching to IgG isotypes; • cellular response to lipopolysaccharide; • positive regulation of transcription by RNA polymerase II; • defense response to protozoan; • response to bacterium; • response to nutrient levels; • response to cobalamin; • response to interferon-gamma; • cellular response to erythropoietin; • cellular response to interleukin-1; • cellular response to tumor necrosis factor; • response to peptide; • inflammatory response; • positive regulation of tyrosine phosphorylation of STAT protein; • positive regulation of blood vessel endothelial cell migration; • positive regulation of angiogenesis; • protein-containing complex assembly;
	Sources:Amigo / QuickGO
直系同源
	958
	21939
	ENSG00000101017
	ENSMUSG00000017652
	P25942
	P27512
NM_001250; NM_001302753; NM_152854; NM_001322421; NM_001322422;
	NM_001362758
	NM_011611; NM_170702; NM_170703; NM_170704
NP_001241; NP_001289682; NP_001309350; NP_001309351; NP_690593;
	NP_001349687
	NP_035741; NP_733803; NP_733804; NP_733805
	維基數據
檢視/編輯人類	檢視/編輯小鼠

分化簇40（Cluster of differentiation 40，簡稱CD40），是一種分布於抗原呈递细胞（APC）的協同刺激因子暨蛋白受體。CD40與輔助型T細胞上的CD154（英语：CD154）（CD40L（英语：CD40L））結合後，抗原呈递细胞會活化，並產生一系列下游反應^[6]。

CD40缺失會造成第三型高IgM症候群（英语：Hyper-IgM syndrome type 3）（Hyper-IgM syndrome type 3）^[6]。

結構及表達

CD40屬於腫瘤壞死因子受體（英语：TNF-receptor）超家族（英语：TNF receptor superfamily）（TNF receptor superfamily）的一員^[6]。含有AT鉤（英语：AT-hook）構型的轉譯因子AKNA（英语：AKNA）可以協同調控CD40及其配體^[7]。

功能

CD40在T細胞相關的免疫和發炎反應具有重要功能，諸如免疫球蛋白類型轉換、記憶B細胞發育，以及生發中心形成^[6]^[8]。 B細胞上也有CD40存在，並會與輔助T細胞上的CD40L結合。CD40和CD40L的橋接可以活化B細胞，降低B細胞接觸到抗原的反應閾值，使其更容易釋放抗體。另外也可以促進B細胞的增殖、同型粘連（homotypic adhesion）、抗體類型轉換。在表面蛋白的表達方面，可以刺激MHC class II（英语：MHC class II）、CD23（英语：CD23）、CD25（英语：CD25）（IL-12R）、CD69（英语：CD69）、CD44等分子的表達，也會使淋巴球功能性抗原1（LFA-1）的轉為高親合態。在細胞週期方面，則會從間期進入S期，開始進行DNA和RNA的複製及合成CD40L^[6]。有研究也發現，要活化β澱粉樣蛋白的微膠細胞也需要CD40和CD40L的連結，因此可能也與阿茲海默症的病生理學相關^[9]。

CD40-CD40L反應在免疫上的角色^[6]
	相關	不相關
一般免疫	T細胞啟動（priming）決定周邊免疫球蛋白的濃度	周邊淋巴器官及次級淋巴器官的淋巴球比例
體液免疫	胸腺依賴性抗原（Thymus dependent antigen）的初級抗體反應胸腺依賴性抗原（Thymus dependent antigen）的次級抗體反應及免疫球蛋白類型轉換記憶B細胞及生發中心的發育	李斯特菌的廓清對抗多醣體的抗體反應
自體免疫	膠原蛋白引起的關節炎狼瘡性腎炎實驗性自體免疫腦炎（Experimental allergic encephalomyelitis）
胞殺作用及移植	急性或慢性移植物對抗宿主疾病（GVHD）異體移植的胞殺作用	抗病毒的胞殺反應抗癌細胞的胞殺反應
T細胞選汰	T細胞的胸腺選汰

交互作用

CD40可以與TRAF2（英语：TRAF2）^[10]^[11]^[12]、TRAF3（英语：TRAF3）^[11]^[13]^[14]^[15]、TRAF6（英语：TRAF6）^[11]^[15]、TRAF5（英语：TRAF5）^[11]^[16]、TTRAP（英语：TTRAP）^[17]產生交互作用。TRAF4家族的蛋白質雖不會直接與CD40作用，但可以間接增加CD40的作用^[18]。

臨床應用

CD40為癌症免疫疗法的潛在標的，目前已經開發出針對該蛋白的刺激性单克隆抗体，以活化樹突細胞刺激抗癌T細胞的途徑，且已有相關論文發表。現有多項臨床研究正在進行^[19]。

參考文獻

^ 與CD40相關的疾病；在維基數據上查看/編輯參考.
^ ^2.0 ^2.1 ^2.2 GRCh38: Ensembl release 89: ENSG00000101017 - Ensembl, May 2017
^ ^3.0 ^3.1 ^3.2 GRCm38: Ensembl release 89: ENSMUSG00000017652 - Ensembl, May 2017
^ Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
^ ^6.0 ^6.1 ^6.2 ^6.3 ^6.4 ^6.5 Laman, Jon D.; Claassen, Eric; Noelle, Randolph J. Functions of CD40 and Its Ligand, gp39 (CD40L). Critical Reviews in Immunology. 2017, 37 (2-6): 371–420 [2021-05-26]. ISSN 1040-8401. doi:10.1615/CritRevImmunol.v37.i2-6.100. （原始内容存档于2021-05-26）（英语）.
^ Siddiqa, A.; Sims-Mourtada, J. C.; Guzman-Rojas, L.; Rangel, R.; Guret, C.; Madrid-Marina, V.; Sun, Y.; Martinez-Valdez, H. Regulation of CD40 and CD40 ligand by the AT-hook transcription factor AKNA. Nature. 2001-03-15, 410 (6826): 383–387 [2021-05-26]. ISSN 0028-0836. PMID 11268217. doi:10.1038/35066602. （原始内容存档于2021-05-26）.
^ Grewal IS, Flavell RA. CD40 and CD154 in cell-mediated immunity. Annual Review of Immunology. 1998, 16: 111–35. PMID 9597126. doi:10.1146/annurev.immunol.16.1.111.
^ Giunta, Brian; Rezai-Zadeh, Kavon; Tan, Jun. Impact of the CD40-CD40L Dyad in Alzheimers Disease. CNS & Neurological Disorders - Drug Targets. 2010-04-01, 9 (2): 149–155. doi:10.2174/187152710791012099 （英语）.
^ McWhirter SM, Pullen SS, Holton JM, Crute JJ, Kehry MR, Alber T. Crystallographic analysis of CD40 recognition and signaling by human TRAF2. Proceedings of the National Academy of Sciences of the United States of America. July 1999, 96 (15): 8408–13. Bibcode:1999PNAS...96.8408M. PMC 17529  . PMID 10411888. doi:10.1073/pnas.96.15.8408.
^ ^11.0 ^11.1 ^11.2 ^11.3 Tsukamoto N, Kobayashi N, Azuma S, Yamamoto T, Inoue J. Two differently regulated nuclear factor kappaB activation pathways triggered by the cytoplasmic tail of CD40. Proceedings of the National Academy of Sciences of the United States of America. February 1999, 96 (4): 1234–9. Bibcode:1999PNAS...96.1234T. PMC 15446  . PMID 9990007. doi:10.1073/pnas.96.4.1234.
^ Malinin NL, Boldin MP, Kovalenko AV, Wallach D. MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1. Nature. February 1997, 385 (6616): 540–4. PMID 9020361. S2CID 4366355. doi:10.1038/385540a0.
^ Hu HM, O'Rourke K, Boguski MS, Dixit VM. A novel RING finger protein interacts with the cytoplasmic domain of CD40. The Journal of Biological Chemistry. December 1994, 269 (48): 30069–72. PMID 7527023.
^ Ni CZ, Welsh K, Leo E, Chiou CK, Wu H, Reed JC, Ely KR. Molecular basis for CD40 signaling mediated by TRAF3. Proceedings of the National Academy of Sciences of the United States of America. September 2000, 97 (19): 10395–9. Bibcode:2000PNAS...9710395N. PMC 27035  . PMID 10984535. doi:10.1073/pnas.97.19.10395.
^ ^15.0 ^15.1 Roy N, Deveraux QL, Takahashi R, Salvesen GS, Reed JC. The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases. The EMBO Journal. December 1997, 16 (23): 6914–25. PMC 1170295  . PMID 9384571. doi:10.1093/emboj/16.23.6914.
^ Ishida TK, Tojo T, Aoki T, Kobayashi N, Ohishi T, Watanabe T, Yamamoto T, Inoue J. TRAF5, a novel tumor necrosis factor receptor-associated factor family protein, mediates CD40 signaling. Proceedings of the National Academy of Sciences of the United States of America. September 1996, 93 (18): 9437–42. Bibcode:1996PNAS...93.9437I. PMC 38446  . PMID 8790348. doi:10.1073/pnas.93.18.9437.
^ Pype S, Declercq W, Ibrahimi A, Michiels C, Van Rietschoten JG, Dewulf N, de Boer M, Vandenabeele P, Huylebroeck D, Remacle JE. TTRAP, a novel protein that associates with CD40, tumor necrosis factor (TNF) receptor-75 and TNF receptor-associated factors (TRAFs), and that inhibits nuclear factor-kappa B activation. The Journal of Biological Chemistry. June 2000, 275 (24): 18586–93. PMID 10764746. doi:10.1074/jbc.M000531200  .
^ Sharma S, Pavlasova GM, Seda V, Cerna KA, Vojackova E, Filip D, Ondrisova L, Sandova V, Kostalova L, Zeni PF, Borsky M, Oppelt J, Liskova K, Kren L, Janikova A, Pospisilova S, Fernandes SM, Shehata M, Rassenti LZ, Jaeger U, Doubek M, Davids MS, Brown JR, Mayer J, Kipps TJ, Mraz M. miR-29 Modulates CD40 Signaling in Chronic Lymphocytic Leukemia by Targeting TRAF4: an Axis Affected by BCR inhibitors. Blood. December 2020. PMID 33171493. doi:10.1182/blood.2020005627  .
^ Vonderheide RH. The Immune Revolution: A Case for Priming, Not Checkpoint. Cancer Cell. April 2018, 33 (4): 563–569. PMC 5898647  . PMID 29634944. doi:10.1016/j.ccell.2018.03.008.

外部連結

Human CD40 genome location and CD40 gene details page in the UCSC Genome Browser（英语：UCSC Genome Browser）.
PDBe-KB （页面存档备份，存于互联网档案馆） provides an overview of all the structure information available in the PDB for Human Tumor necrosis factor receptor superfamily member 5 (CD40)

延伸閱讀

Parham P. The Immune System 2nd. Garland Science. 2004: 169–173. ISBN 978-0-8153-4093-5.
Wang JH, Zhang YW, Zhang P, Deng BQ, Ding S, Wang ZK, Wu T, Wang J. CD40 ligand as a potential biomarker for atherosclerotic instability. Neurological Research. September 2013, 35 (7): 693–700. PMC 3770830  . PMID 23561892. doi:10.1179/1743132813Y.0000000190.
Banchereau J, Bazan F, Blanchard D, Brière F, Galizzi JP, van Kooten C, Liu YJ, Rousset F, Saeland S. The CD40 antigen and its ligand. Annual Review of Immunology. 1994, 12: 881–922. PMID 7516669. doi:10.1146/annurev.iy.12.040194.004313.
van Kooten C, Banchereau J. CD40-CD40 ligand. Journal of Leukocyte Biology. January 2000, 67 (1): 2–17. PMID 10647992. S2CID 35592719. doi:10.1002/jlb.67.1.2.
Schattner EJ. CD40 ligand in CLL pathogenesis and therapy. Leukemia & Lymphoma. May 2000, 37 (5–6): 461–72. PMID 11042507. S2CID 39398949. doi:10.3109/10428190009058499.
Bhushan A, Covey LR. CD40:CD40L interactions in X-linked and non-X-linked hyper-IgM syndromes. Immunologic Research. 2002, 24 (3): 311–24. PMID 11817328. S2CID 19537892. doi:10.1385/IR:24:3:311.
Cheng G, Schoenberger SP. CD40 signaling and autoimmunity. Signal Transduction Pathways in Autoimmunity. Current Directions in Autoimmunity 5. 2002: 51–61. ISBN 978-3-8055-7308-5. PMID 11826760. doi:10.1159/000060547.
Dallman C, Johnson PW, Packham G. Differential regulation of cell survival by CD40. Apoptosis. January 2003, 8 (1): 45–53. PMID 12510151. S2CID 22461134. doi:10.1023/A:1021696902187.
O'Sullivan B, Thomas R. Recent advances on the role of CD40 and dendritic cells in immunity and tolerance. Current Opinion in Hematology. July 2003, 10 (4): 272–8. PMID 12799532. S2CID 43043879. doi:10.1097/00062752-200307000-00004.
Benveniste EN, Nguyen VT, Wesemann DR. Molecular regulation of CD40 gene expression in macrophages and microglia. Brain, Behavior, and Immunity. January 2004, 18 (1): 7–12. PMID 14651941. S2CID 8081107. doi:10.1016/j.bbi.2003.09.001.
Xu Y, Song G. The role of CD40-CD154 interaction in cell immunoregulation. Journal of Biomedical Science. 2005, 11 (4): 426–38. PMID 15153777. S2CID 202658036. doi:10.1159/000077892.
Contin C, Couzi L, Moreau JF, Déchanet-Merville J, Merville P. [Immune dysfuntion of uremic patients: potential role for the soluble form of CD40]. Nephrologie. 2004, 25 (4): 119–26. PMID 15291139.

[1] 與CD40相關的疾病；在維基數據上查看/編輯參考.

[refGRCh38Ensembl-2] 2.0 ^2.1 ^2.2 GRCh38: Ensembl release 89: ENSG00000101017 - Ensembl, May 2017

[refGRCm38Ensembl-3] 3.0 ^3.1 ^3.2 GRCm38: Ensembl release 89: ENSMUSG00000017652 - Ensembl, May 2017

[4] Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.

[5] Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.

[:0-6] 6.0 ^6.1 ^6.2 ^6.3 ^6.4 ^6.5 Laman, Jon D.; Claassen, Eric; Noelle, Randolph J. Functions of CD40 and Its Ligand, gp39 (CD40L). Critical Reviews in Immunology. 2017, 37 (2-6): 371–420 [2021-05-26]. ISSN 1040-8401. doi:10.1615/CritRevImmunol.v37.i2-6.100. （原始内容存档于2021-05-26）（英语）.

[7] Siddiqa, A.; Sims-Mourtada, J. C.; Guzman-Rojas, L.; Rangel, R.; Guret, C.; Madrid-Marina, V.; Sun, Y.; Martinez-Valdez, H. Regulation of CD40 and CD40 ligand by the AT-hook transcription factor AKNA. Nature. 2001-03-15, 410 (6826): 383–387 [2021-05-26]. ISSN 0028-0836. PMID 11268217. doi:10.1038/35066602. （原始内容存档于2021-05-26）.

[8] Grewal IS, Flavell RA. CD40 and CD154 in cell-mediated immunity. Annual Review of Immunology. 1998, 16: 111–35. PMID 9597126. doi:10.1146/annurev.immunol.16.1.111.

[9] Giunta, Brian; Rezai-Zadeh, Kavon; Tan, Jun. Impact of the CD40-CD40L Dyad in Alzheimers Disease. CNS & Neurological Disorders - Drug Targets. 2010-04-01, 9 (2): 149–155. doi:10.2174/187152710791012099 （英语）.

[pmid10411888-10] McWhirter SM, Pullen SS, Holton JM, Crute JJ, Kehry MR, Alber T. Crystallographic analysis of CD40 recognition and signaling by human TRAF2. Proceedings of the National Academy of Sciences of the United States of America. July 1999, 96 (15): 8408–13. Bibcode:1999PNAS...96.8408M. PMC 17529  . PMID 10411888. doi:10.1073/pnas.96.15.8408.

[pmid9990007-11] 11.0 ^11.1 ^11.2 ^11.3 Tsukamoto N, Kobayashi N, Azuma S, Yamamoto T, Inoue J. Two differently regulated nuclear factor kappaB activation pathways triggered by the cytoplasmic tail of CD40. Proceedings of the National Academy of Sciences of the United States of America. February 1999, 96 (4): 1234–9. Bibcode:1999PNAS...96.1234T. PMC 15446  . PMID 9990007. doi:10.1073/pnas.96.4.1234.

[pmid9020361-12] Malinin NL, Boldin MP, Kovalenko AV, Wallach D. MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1. Nature. February 1997, 385 (6616): 540–4. PMID 9020361. S2CID 4366355. doi:10.1038/385540a0.

[pmid7527023-13] Hu HM, O'Rourke K, Boguski MS, Dixit VM. A novel RING finger protein interacts with the cytoplasmic domain of CD40. The Journal of Biological Chemistry. December 1994, 269 (48): 30069–72. PMID 7527023.

[pmid10984535-14] Ni CZ, Welsh K, Leo E, Chiou CK, Wu H, Reed JC, Ely KR. Molecular basis for CD40 signaling mediated by TRAF3. Proceedings of the National Academy of Sciences of the United States of America. September 2000, 97 (19): 10395–9. Bibcode:2000PNAS...9710395N. PMC 27035  . PMID 10984535. doi:10.1073/pnas.97.19.10395.

[pmid9384571-15] 15.0 ^15.1 Roy N, Deveraux QL, Takahashi R, Salvesen GS, Reed JC. The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases. The EMBO Journal. December 1997, 16 (23): 6914–25. PMC 1170295  . PMID 9384571. doi:10.1093/emboj/16.23.6914.

[pmid8790348-16] Ishida TK, Tojo T, Aoki T, Kobayashi N, Ohishi T, Watanabe T, Yamamoto T, Inoue J. TRAF5, a novel tumor necrosis factor receptor-associated factor family protein, mediates CD40 signaling. Proceedings of the National Academy of Sciences of the United States of America. September 1996, 93 (18): 9437–42. Bibcode:1996PNAS...93.9437I. PMC 38446  . PMID 8790348. doi:10.1073/pnas.93.18.9437.

[pmid10764746-17] Pype S, Declercq W, Ibrahimi A, Michiels C, Van Rietschoten JG, Dewulf N, de Boer M, Vandenabeele P, Huylebroeck D, Remacle JE. TTRAP, a novel protein that associates with CD40, tumor necrosis factor (TNF) receptor-75 and TNF receptor-associated factors (TRAFs), and that inhibits nuclear factor-kappa B activation. The Journal of Biological Chemistry. June 2000, 275 (24): 18586–93. PMID 10764746. doi:10.1074/jbc.M000531200  .

[pmid33171493-18] Sharma S, Pavlasova GM, Seda V, Cerna KA, Vojackova E, Filip D, Ondrisova L, Sandova V, Kostalova L, Zeni PF, Borsky M, Oppelt J, Liskova K, Kren L, Janikova A, Pospisilova S, Fernandes SM, Shehata M, Rassenti LZ, Jaeger U, Doubek M, Davids MS, Brown JR, Mayer J, Kipps TJ, Mraz M. miR-29 Modulates CD40 Signaling in Chronic Lymphocytic Leukemia by Targeting TRAF4: an Axis Affected by BCR inhibitors. Blood. December 2020. PMID 33171493. doi:10.1182/blood.2020005627  .

[19] Vonderheide RH. The Immune Revolution: A Case for Priming, Not Checkpoint. Cancer Cell. April 2018, 33 (4): 563–569. PMC 5898647  . PMID 29634944. doi:10.1016/j.ccell.2018.03.008.

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