Your Good Partner in Biology Research

DSG2:橋粒芯蛋白家族DSGs表達最廣泛的成員,心肌病、腺病毒和腫瘤新興靶點?

日期:2023-05-15 16:52:35

DSG2是一種跨膜糖蛋白,屬于鈣粘蛋白家族中的橋粒芯蛋白家族DSGs成員。多種橋粒蛋白的突變均可導(dǎo)致心肌病的發(fā)生,包括如DSG2、Desmocollin-2(DSC2)、Desmoplakin(DSP)和Plakophilin-2(PKP2)等。其中,DSG2基因突變?yōu)檩^常見的誘因之一。越來越多的證據(jù)顯示,DSG2在某些惡性腫瘤中也具有重要作用,并與惡性程度和預(yù)后密切相關(guān)。近期研究還揭示,DSG2是人55型腺病毒HAdV55的主要受體;另有報道,DSG2調(diào)控細(xì)胞外泌體EVs釋放,從而調(diào)節(jié)腫瘤微環(huán)境,促進腫瘤進展。

目前,已有研究顯示,部分藥物或DSGs抗體可以針對DSGs的表達和功能進行調(diào)節(jié),達到治療疾病的目的。DSG2作為橋粒芯蛋白家族DSGs表達最廣泛的成員,未來,進一步探索DSG2在生理和病理過程中的作用,將為心肌病、腺病毒和腫瘤等疾病治療提供一個極具潛力的新研究方向。


1. 橋粒芯蛋白家族DSGs

橋粒芯蛋白家族(Desmogleins,DSGs)作為細(xì)胞表面跨膜蛋白,是組成細(xì)胞緊密連接—橋粒結(jié)構(gòu)的重要部分。橋粒芯蛋白家族DSGs共有4種亞型(DSG1、DSG2、DSG3、DSG4),與橋粒膠蛋白家族(Desmocollins,DSCs)的3種亞型(DSC1DSC2、DSC3)一起組成了橋粒鈣黏素家族。這些蛋白與橋粒斑蛋白DSP等共同構(gòu)成細(xì)胞黏附結(jié)構(gòu)—橋粒或半橋粒,其中橋粒芯蛋白家族DSGs作為關(guān)鍵蛋白,調(diào)節(jié)相鄰細(xì)胞間的聯(lián)合,在細(xì)胞間的黏附和信息傳遞過程中發(fā)揮著重要的作用 [1-3]。

在人體中,橋粒芯蛋白DSGs主要存在于表皮、毛囊、指甲和心臟等組織中 [4]。DSGs被發(fā)現(xiàn)在皮膚、黏膜、心臟、遺傳性疾病、自身免疫性以及腫瘤等多種疾病中出現(xiàn)表達或功能異常。已有研究表明,通過調(diào)節(jié)DSGs的表達可以有效地治療天皰瘡、心肌病和腫瘤 [5-7]。因此,橋粒芯蛋白家族DSGs有望成為多種重大疾病治療的新靶點。


2. 什么是DSG2?

2.1 DSG2的結(jié)構(gòu)

橋粒芯糖蛋白2(Desmoglein 2,DSG2),又名ARVC10、ARVD10、CDHF5、CMD1BB。DSG2作為橋粒芯家族DSGs成員,參與橋粒結(jié)構(gòu)組成,對橋粒結(jié)構(gòu)裝配和穩(wěn)定起到重要作用。橋粒與細(xì)胞黏附連接有關(guān),黏附連接在腫瘤的發(fā)展中起著重要作用。DSG2蛋白結(jié)構(gòu)主要包括:胞外4個鈣黏蛋白重復(fù)區(qū)(EC1-4)、跨膜區(qū)TM、胞內(nèi)鈣黏蛋白片段ICD、富含脯氨酸連接序列LD、重復(fù)單元區(qū)RUD和終末端富含甘氨酸區(qū)TD(圖1[8]。

DSG2結(jié)構(gòu)示意圖

圖1. DSG2結(jié)構(gòu)示意圖 [8]

2.2 DSG2的表達

DSG2蛋白是橋粒芯蛋白家族DSGs中分布最為廣泛的亞型,在含有橋粒的組織中均會出現(xiàn)。許多上皮、非上皮起源的組織均發(fā)現(xiàn)其表達,如腦、心臟、肝、骨骼肌、皮膚、結(jié)腸、膀胱、胃、心肌、淋巴濾泡樹突網(wǎng) [9-10]?,F(xiàn)有研究發(fā)現(xiàn),DSG2異常表達與多種腫瘤相關(guān),如胃癌、皮膚癌、乳腺癌、食管鱗狀細(xì)胞癌、前列腺癌、胰腺癌、多發(fā)性骨髓瘤等 [11-14]。

2.3 DSG2的功能

DSG2被認(rèn)為是橋粒中最重要的結(jié)構(gòu)。DSG2除了維持細(xì)胞間粘附性和保持組織的完整性,還可調(diào)節(jié)許多細(xì)胞進程,包括細(xì)胞增殖、分化、細(xì)胞凋亡、組織形成等。研究發(fā)現(xiàn),DSG2突變會導(dǎo)致黏附力破壞,可引起心臟閏盤結(jié)構(gòu)發(fā)生變化,導(dǎo)致心律失常性右室心肌病ARVC或擴張性心肌病DCM [15-16];DSG2通過C SrcCav1依賴性機制正向調(diào)節(jié)EGFR信號通路來刺激細(xì)胞生長和遷移 [17];胚胎著床時,DSG2基因缺失可引起胚胎干細(xì)胞增殖缺陷,誘導(dǎo)胚胎干細(xì)胞死亡 [18-19]


3. DSG2相關(guān)的信號通路

DSG2在多種腫瘤中的表達發(fā)生改變。然而,不同類型腫瘤中,DSG2的表達情況以及腫瘤如何調(diào)節(jié)并克服粘附分子的作用還缺乏完整的認(rèn)識。普遍認(rèn)為惡性腫瘤的浸潤和轉(zhuǎn)移與細(xì)胞粘附性缺失相關(guān),許多疾病伴發(fā)橋粒蛋白的改變。一些研究提示,DSG2蛋白通過改變橋粒連接的結(jié)構(gòu)和功能,調(diào)節(jié)細(xì)胞間粘附性,促進或抑制腫瘤侵襲和轉(zhuǎn)移。

在結(jié)直腸癌中,沉默DSG2表達,可改變EGFR的磷酸化狀態(tài)及其下游細(xì)胞外信號調(diào)節(jié)激酶活性,抑制EGFR信號通路和細(xì)胞增殖 [20]。在皮膚癌中,DSG2的過表達激活多條信號通路,如PI3-kinase/AKT、MEK/MAPKNF-κB,從而促進癌細(xì)胞增殖導(dǎo)致惡性轉(zhuǎn)化 [21-23]。在前列腺癌中,Snail介導(dǎo)E-cadherin轉(zhuǎn)錄抑制,而對DSG2表達無影響 [24]。

在卵巢癌中,敲除CD133的卵巢透明細(xì)胞癌干細(xì)胞中,DSG2表達顯著下調(diào),表明DSG2可能參與干細(xì)胞的惡性轉(zhuǎn)化 [25-26]。在宮頸癌中,E鈣黏蛋白在轉(zhuǎn)錄水平出現(xiàn)下調(diào)后,DSG2蛋白結(jié)構(gòu)發(fā)生改變,導(dǎo)致細(xì)胞間黏附功能減弱,促進高級別鱗狀上皮內(nèi)病變的發(fā)生 [27]。在肺腺癌中,DSG2通過EGFR/Src/PAK1通路調(diào)控癌細(xì)胞的進展,其高表達可增加腫瘤對奧西美替尼(Osimertinib)的耐藥性(圖2[28]。

DSG2參與靶向藥物Osimertinib耐藥機制

圖2. DSG2參與靶向藥物Osimertinib耐藥機制 [28]


4. DSG2與哪些疾病相關(guān)?

DSG2作為橋粒結(jié)構(gòu)中主要介導(dǎo)細(xì)胞黏附力的跨膜糖蛋白,其突變與心肌疾病、腸道炎癥等疾病有直接關(guān)系。在多種腫瘤細(xì)胞中證實,DSG2異常缺失所導(dǎo)致的細(xì)胞黏附力下降,與癌細(xì)胞侵襲遷移能力增強以及癌癥的不良預(yù)后密切相關(guān)。

4.1 DSG2和心肌疾病

在小鼠模型中,DSG2突變雜交鼠出現(xiàn)類似心律失常右室心肌病ARVC患者的臨床表現(xiàn):心室擴大、室壁變薄、心功能下降、炎性反應(yīng)和心室纖維化等。ARVC的早期臨床診斷一直是個難題,主要依靠超聲心電圖,然而超聲心電圖的診斷不具有特異性。DSG2基因突變有可能作為臨床ARVC患者的檢測指標(biāo) [29]。

4.2 DSG2和腸道疾病

研究發(fā)現(xiàn)KLF5敲低可干擾DSG2表達,使得細(xì)胞橋粒結(jié)構(gòu)被破壞,嚴(yán)重?fù)p害小鼠腸道的屏障功能,從而導(dǎo)致炎癥性腸病的發(fā)生。在克羅恩病和潰瘍性結(jié)腸炎的患者中,DSG2和緊密連接蛋白Claudin1表達明顯下調(diào),此過程可能受到TNF的調(diào)控。特異結(jié)合DSG2結(jié)構(gòu)域的串聯(lián)多肽(Tandem Peptide,TP)的加入,可穩(wěn)定DSG2的結(jié)構(gòu)并干擾TNF誘導(dǎo)的腸上皮滲透性增高的現(xiàn)象 [30]

目前,腸道炎癥疾病,尤其是克羅恩病和潰瘍性結(jié)腸炎,主要通過糖皮質(zhì)激素治療,相對不良反應(yīng)較大。因此,DSG2在腸道炎癥疾病中的作用和機制研究,有望為該類疾病治療提供新途徑。

4.3 DSG2和腺病毒感染

在腺病毒亞型中,3,7,11,14亞型以及新亞型14p1,通過特異結(jié)合上皮細(xì)胞DSG2受體,導(dǎo)致感染的發(fā)生。在小鼠的人DSG2轉(zhuǎn)基因模型中,帶有重組二聚體腺病毒3型纖維紐結(jié)JO-1的腺病毒可通過識別DSG2受體,促進DSG2的胞外域降解,轉(zhuǎn)移入胞,從而降低細(xì)胞間連接 [31-32]。另有報道,DSG2是人腺病毒HAdV-B55導(dǎo)致成人社區(qū)獲得性肺炎CAP的主要受體,這對于了解腺病毒與宿主細(xì)胞之間的相互作用具有重要意義 [33]。

4.4 DSG2和腫瘤

越來越多的研究發(fā)現(xiàn),DSG2對于腫瘤有重要影響。例如,DSG2蛋白在部分上皮性腫瘤,包括鱗癌、基底細(xì)胞癌、黑色素瘤、結(jié)腸癌、小細(xì)胞肺癌等均異常高表達。然而,DSG2在胃癌、胰腺癌、膽囊癌中低表達,提示DSG2在不同腫瘤的發(fā)生和發(fā)展中發(fā)揮不同作用。

在胰腺癌中DSG2表達明顯下降,細(xì)胞內(nèi)聚力喪失,腫瘤細(xì)胞增殖侵襲遷移能力增強,同時激肽釋放酶(Kallikrein7,KLK7)明顯高表達,通過降解實驗表明DSG2的表達降低與KLK7有關(guān),KLK7可促進DSG2降解成多個片段,而KLK7抑制劑可阻斷此過程 [34]。

在多例胃癌臨床標(biāo)本中,DSG2表達明顯降低,且與胃癌患者不良預(yù)后明顯相關(guān) [35]

在鱗癌中EGFR和ADAM均可通過促進DSG2的降解脫落入胞,減少癌細(xì)胞黏附,促進細(xì)胞遷移 [36]。

在惡性黑色素瘤中DSG2的表達和不良預(yù)后密切相關(guān),且可調(diào)控血管生成擬態(tài)(Vasculogenic mimicry,VM)。因此,DSG2作為黑色素瘤中VM活性的重要調(diào)節(jié)因子,針對DSG2的靶向治療,有可能抑制腫瘤的血液供應(yīng)和轉(zhuǎn)移擴散 [37]。

在頭頸部鱗狀細(xì)胞癌中,首次發(fā)現(xiàn)其外泌體(extracellular vesicles,EVs)富含有DSG2蛋白的C端片段,DSG2異常高表達促進EVs釋放促有絲分裂的相關(guān)因子,如表皮生長因子受體C-Src等。同時,其循環(huán)血液中被釋放的EVs中DSG2也更加豐富,這為癌癥診斷提供了新的途徑 [38-39]。

總體而言,DSG2不僅可作為黏附分子調(diào)節(jié)細(xì)胞間黏附,還可調(diào)節(jié)外泌體的分泌和旁分泌信號,并改變外泌體,使之分泌更多促有絲分裂相關(guān)因子,影響腫瘤微環(huán)境,促進腫瘤細(xì)胞生長。


5. DSG2的臨床在研藥物

來自Pharmsnap的最新數(shù)據(jù)表明,臺灣全福生物科技股份有限公司(BRM-131)和美國Renovacor, Inc.(DSG2 AAV gene therapy)這兩家公司正在開展針對DSG2的藥物研發(fā),目前處于藥物發(fā)現(xiàn)階段。DSG2作為橋粒結(jié)構(gòu)中不可分割的組成部分,其缺失可能導(dǎo)致自身免疫性疾病、感染性疾病和遺傳性疾病,并影響相關(guān)組織的功能。越來越多的研究已表明,DSG2基因突變和表達水平變化會影響腫瘤細(xì)胞增殖,使其成為多種腫瘤的早期預(yù)警標(biāo)志。

同時,利用DSG2靶向治療并研究其所影響的信號通路,將有望提高DSG2誘導(dǎo)疾病的傳統(tǒng)藥物的治療效果。目前,DSG2作為橋粒芯蛋白家族中表達廣泛的跨膜蛋白,在心肌病、腸道炎癥、腺病毒以及腫瘤等疾病的治療上成為了一個新興靶點。

為鼎力協(xié)助各藥企針對DSG2在心肌病、腸道炎癥、腺病毒以及腫瘤等疾病在臨床中的研究,CUSABIO推出DSG2活性蛋白產(chǎn)品(CSB-MP622752HU),助力您在DSG2機制方面的研究或其潛在臨床價值的探索(點擊查看DSG2系列產(chǎn)品:DSG2蛋白 ;DSG2 抗體)。

DSG2 蛋白:

Recombinant Human Desmoglein-2(DSG2),partial (Active)

High Purity Validated by SDS-PAGE

The purity was greater than 96.3% as determined by SDS-PAGE. (Tris-Glycine gel) Discontinuous SDS-PAGE (reduced) with 5% enrichment gel and 15% separation gel.

Excellent Bioactivity Validated by Functional ELISA

Immobilized Human DSG2 at 2μg/mL can bind Anti-DSG2 recombinant antibody (CSB-RA622752MA1HU), the EC50 is 20.26-38.00 ng/mL.


參考文獻:

[1] Hegazy, Marihan, et al. "Desmosomal cadherins in health and disease." Annual Review of Pathology: Mechanisms of Disease 17 (2022): 47-72.

[2] Kosaka, K., et al. "Pemphigus vegetans with antibodies against desmoglein 1 and desmocollin 1-3: a case report and literature review." Journal of the European Academy of Dermatology and Venereology 36.12 (2022): e998-e1000.

[3] Sokol, Ena. "Structure of desmosomes." Autoimmune Bullous Diseases: Text and Review. cham: Springer International Publishing, 2022. 61-64.

[4] Myo Min, Kay K., et al. "Desmoglein-2 is important for islet function and β-cell survival." Cell Death & Disease 13.10 (2022): 911.

[5] Zhao, W. L., et al. "Analysis of clinical characteristics, prognosis and antibody pathogenicity of pemphigus patients positive for anti desmoglein IgG autoantibodies in remission: a retrospective cohort study." Journal of the European Academy of Dermatology and Venereology 36.2 (2022) : 271-278. : 271-278.

[6] Yanqing, L. I., et al. "Research progress in the function of desmoglein-2 in digestive system tumors." JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE) 42.2 (2022): 247.

[7] Shiba, Mikio, et al. "Phenotypic recapitulation and correction of desmoglein-2-deficient cardiomyopathy using human-induced pluripotent stem cell -derived cardiomyocytes." Human Molecular Genetics 30.15 (2021): 1384-1397.

[8] Hawthorne, Robert N., et al. "Altered electrical, biomolecular, and immunologic phenotypes in a novel patient-derived stem cell model of desmoglein-2 mutant ARVC." Journal of Clinical Medicine 10.14 (2021): 3061.

[9] Debus, Jana Davina, et al. "In vitro analysis of arrhythmogenic cardiomyopathy associated desmoglein-2 (DSG2) mutations reveals diverse glycosylation patterns." journal of molecular and cellular cardiology 129 (2019): 303-313.

[10] Yang, Tingting, et al. "DSG2 expression is low in colon cancer and correlates with poor survival." bmc gastroenterology 21.1 (2021): 1-10.

[11] Qin, Shuhang, et al. "DSG2 expression is correlated with poor prognosis and promotes early-stage cervical cancer." Cancer Cell International 20 (2020) : 1-13.

[12] Lee, Kyungmin, et al. "Dsg2-mediated c-Met activation in anaplastic thyroid cancer motility and invasion." Endocrine-Related Cancer 27.11 (2020). 601-614.

[13] Yang, Tingting, et al. "DSG2 expression is low in colon cancer and correlates with poor survival." bmc gastroenterology 21.1 (2021): 1-10.

[14] Zhou, Bing-Xia, and Yan Li. "Significance of desmoglein-2 on cell malignant behaviors via mediating MAPK signaling in cervical cancer." The Kaohsiung journal of medical sciences 36.5 (2020): 336-343.

[15] Chen, Liang, et al. "A founder homozygous DSG2 variant in East Asia results in ARVC with full penetrance and heart failure phenotype." International Journal of Cardiology 274 (2019): 263-270.

[16] Kuo, Kelly, Rosa Speranza, and Rinat Hackmon. "Fetal dilated cardiomyopathy associated with variants of uncertain significance in MYH7 and DSG2 genes. A case report and review of the literature." Journal of Obstetrics and Gynaecology Canada 42.9 (2020): 1147-1150.

[17] Overmiller, Andrew M., et al. "c-Src/Cav1-dependent activation of the EGFR by Dsg2." Oncotarget 7.25 (2016): 37536.

[18] Chen, Ling, et al. "Up-regulation of Dsg2 conferred stem cells with malignancy through wnt/β-catenin signaling pathway. "Experimental Cell Research 422.1 (2023): 113416.

[19] Eshkind, Leonid, et al. "Loss of desmoglein 2 suggests essential functions for early embryonic development and proliferation of embryonal stem cells." European journal of cell biology 81.11 (2002): 592-598.

[20] Kamekura, R., et al. "Loss of the desmosomal cadherin desmoglein-2 suppresses colon cancer cell proliferation through EGFR signaling." oncogene 33.36 (2014): 4531-4536.

[21] Zhou, Bing-Xia, and Yan Li. "Significance of desmoglein-2 on cell malignant behaviors via mediating MAPK signaling in cervical cancer." The Kaohsiung journal of medical sciences 36.5 (2020): 336-343.

[22] Lin, Yen-Nien, et al. "Extracellular vesicles from immortalized cardiosphere-derived cells attenuate arrhythmogenic cardiomyopathy in desmoglein -2 mutant mice." European Heart Journal 42.35 (2021): 3558-3571.

[23] Brennan, Donna, and M? G. Mahoney. "Increased expression of Dsg2 in malignant skin carcinomas: A tissue-microarray based study." Cell adhesion & migration 3.2 (2009): 148-154.

[24] Barber, Alison G., et al. "PI 3K/AKT pathway regulates E-cadherin and Desmoglein 2 in aggressive prostate cancer." cancer medicine 4.8 ( 2015): 1258-1271.

[25] Kim, Jiho, et al. "Desmoglein-2 as a prognostic and biomarker in ovarian cancer." Cancer Biology & Therapy 21.12 (2020): 1154-1162.

[26] Gonzalez-Pastor, Rebeca, Peter S. Goedegebuure, and David T. Curiel. "Understanding and addressing barriers to successful adenovirus-based virotherapy for ovarian cancer." Cancer gene therapy 28.5 (2021): 375-389.

[27] Qin, Shuhang, et al. "DSG2 expression is correlated with poor prognosis and promotes early-stage cervical cancer." Cancer Cell International 20 (2020) : 1-13.

[28] Jin, Runsen, et al. "Desmoglein-2 modulates tumor progression and osimertinib drug resistance through the EGFR/Src/PAK1 pathway in lung adenocarcinoma." Cancer Letters 483 (2020): 46-58.

[29] Chen, Liang, et al. "A founder homozygous DSG2 variant in East Asia results in ARVC with full penetrance and heart failure phenotype." International Journal of Cardiology 274 (2019): 263-270.

[30] Schlegel, Nicolas, Kevin Boerner, and Jens Waschke. "Targeting desmosomal adhesion and signalling for intestinal barrier stabilization in inflammatory bowel diseases-Lessons from experimental models and patients." Acta physiologica 231.1 (2021): e13492.

[31] Wang, Hongjie, et al. "Structural and functional studies on the interaction of adenovirus fiber knobs and desmoglein 2." journal of virology 87.21 (2013 ): 11346-11362.

[32] Wang, Hongjie, et al. "Intracellular signaling and desmoglein 2 shedding triggered by human adenoviruses Ad3, Ad14, and Ad14P1." journal of virology 89.21 (2015): 10841-10859.

[33] Zhang, Jing, et al. "Desmoglein 2 (DSG2) is a receptor of human adenovirus type 55 causing adult severe community-acquired pneumonia." Virologica Sinica 36 (2021): 1400-1410.

[34] Ramani, Vishnu C., Leah Hennings, and Randy S. Haun. "Desmoglein 2 is a substrate of kallikrein 7 in pancreatic cancer." BMC cancer 8.1 (2008): 1-10.

[35] Klessner, Jodi L., et al. "EGFR and ADAMs cooperate to regulate shedding and endocytic trafficking of the desmosomal cadherin desmoglein 2." Molecular biology of the cell 20.1 (2009): 328-337.

[36] Liu, Yin-Qiao, et al. "Serum DSG2 as a potential biomarker for diagnosis of esophageal squamous cell carcinoma and esophagogastric junction adenocarcinoma." Bioscience Reports 42.5 (2022): BSR20212612.

[37] Tan, Lih Yin, et al. "Desmoglein 2 promotes vasculogenic mimicry in melanoma and is associated with poor clinical outcome." Oncotarget 7.29 (2016). 46492.

[38] Overmiller, Andrew M., et al. "c-Src/Cav1-dependent activation of the EGFR by Dsg2." Oncotarget 7.25 (2016): 37536.

[39] Overmiller, Andrew M., et al. "Desmoglein 2 modulates extracellular vesicle release from squamous cell carcinoma keratinocytes." The FASEB Journal 31.8 (2017): 3412.

特別關(guān)注