轉(zhuǎn)鐵蛋白受體TFR1（TFRC）：鐵穩(wěn)態(tài)關(guān)鍵成員，貧血、神經(jīng)退行性疾病、癌癥新銳靶點(diǎn)！
日期：2024-10-23 16:01:00
轉(zhuǎn)鐵蛋白受體TFR1是介導(dǎo)鐵離子進(jìn)入細(xì)胞通道的關(guān)鍵成員之一，在調(diào)節(jié)細(xì)胞鐵代謝和維持鐵平衡中發(fā)揮關(guān)鍵作用。癌細(xì)胞為了快速增殖需要大量鐵，導(dǎo)致細(xì)胞表面轉(zhuǎn)鐵蛋白受體1（TfR1）顯著上調(diào)，TfR1通過(guò)與攜鐵蛋白轉(zhuǎn)鐵蛋白結(jié)合來(lái)介導(dǎo)鐵的攝取。利用這一現(xiàn)象和 TfR1 的快速內(nèi)吞速率，美國(guó)丹娜-法伯癌癥研究所Xin Zhou課題組開(kāi)發(fā)了轉(zhuǎn)鐵蛋白受體靶向嵌合體（TransTAC），這是一種用于膜蛋白降解的異雙特異性抗體模式 [1]。TransTAC被設(shè)計(jì)用于驅(qū)動(dòng)感興趣的靶蛋白與TfR1從細(xì)胞表面共同內(nèi)吞，并促使靶蛋白進(jìn)入溶酶體降解途徑。這一研究于2024年9月25日發(fā)表在Nature上，TransTAC代表了一類有前景的新型雙功能抗體家族，可用于精確調(diào)控膜蛋白和靶向癌癥治療。
現(xiàn)有研究證實(shí)，TFR1在許多腫瘤細(xì)胞中高表達(dá)，是潛在的腫瘤標(biāo)志物，且針對(duì)TFR1進(jìn)行治療可以有效地抑制腫瘤生長(zhǎng)和轉(zhuǎn)移。此外，TFR1還與其它疾病如貧血、鐵代謝障礙性疾病等有關(guān)。因此，以TFR1為靶點(diǎn)的治療策略來(lái)靶向調(diào)節(jié)細(xì)胞內(nèi)鐵水平，可以在相關(guān)疾病的臨床應(yīng)用中發(fā)揮重要作用。
1. 什么是TFR1？
1.1 TFR1的結(jié)構(gòu)
轉(zhuǎn)鐵蛋白受體1（Transferrin receptor protein 1，TFR1）也被稱為CD71或TFRC。TFR1/TFRC是一種II型跨膜蛋白，是調(diào)節(jié)細(xì)胞內(nèi)鐵元素轉(zhuǎn)運(yùn)過(guò)程的最重要膜蛋白。TFR1是由兩個(gè)同源二聚體的亞基通過(guò)二硫鍵交聯(lián)而成。每個(gè)單體包含一個(gè)大的胞外C端區(qū)域，一個(gè)單跨膜區(qū)域及一個(gè)短的N端區(qū)域。C端區(qū)域作為外功能區(qū)，包含了與轉(zhuǎn)鐵蛋白（Transferrin，Tf）相結(jié)合的位點(diǎn)（圖1） [2-4]。目前已發(fā)現(xiàn)兩種轉(zhuǎn)鐵蛋白受體，分別是TFR1和TFR2，它們?cè)诮Y(jié)構(gòu)和功能上都比較相似。在正常生理?xiàng)l件下，TFR1與轉(zhuǎn)鐵蛋白Tf發(fā)生相互作用，促進(jìn)鐵的吸收。這種結(jié)合形式是血液中鐵的主要存在方式 [5-6]。
圖1. TFR1的結(jié)構(gòu) [2]
1.2 TFR1的表達(dá)
TFR1是一種廣泛表達(dá)于人體幾乎所有細(xì)胞和組織類型中的膜蛋白。TFR1在人體需要鐵元素時(shí)發(fā)揮作用，介導(dǎo)鐵離子的轉(zhuǎn)運(yùn)和代謝。TFR1的表達(dá)廣泛分布于免疫系統(tǒng)、造血系統(tǒng)（如骨髓干細(xì)胞、紅細(xì)胞和白細(xì)胞）、神經(jīng)系統(tǒng)（如神經(jīng)元和神經(jīng)膠質(zhì)細(xì)胞）、生殖系統(tǒng)、心臟、肝臟、腎臟等各種組織和細(xì)胞類型。TFR1的表達(dá)水平受多種因素影響，包括細(xì)胞內(nèi)鐵含量、細(xì)胞分化狀態(tài)、激素調(diào)節(jié)以及炎癥狀態(tài)等 [7-9]。
1.3 TFR1的功能
TFR1最主要的生理功能是與轉(zhuǎn)鐵蛋白（transferrin，Tf）結(jié)合，通過(guò)內(nèi)吞方式介導(dǎo)細(xì)胞對(duì)鐵的攝取。因此，Tf-TFR1系統(tǒng)被認(rèn)為是機(jī)體獲取鐵離子的重要途徑。具體而言，首先，Tf和鐵離子（Fe3+或Fe2+形式）結(jié)合后，其空間結(jié)構(gòu)隨之發(fā)生相應(yīng)變化，將鐵離子包入蛋白內(nèi)形成Tf-Fe2+。其次，TFR1在生理pH下與Tf-Fe2+結(jié)合，Tf-TFR1復(fù)合物被網(wǎng)格蛋白（Clathrin）通過(guò)小窩的內(nèi)吞作用內(nèi)部化（圖2） [10-12]。
隨之，胞內(nèi)Tf-TFR1復(fù)合物被運(yùn)輸至內(nèi)體酸化，TFR1和Tf的氨基酸殘基相互作用，引起構(gòu)象改變促使鐵離子釋放，TFR1通過(guò)高爾基復(fù)合體循環(huán)至細(xì)胞表面完成鐵離子運(yùn)輸。總之，TFR1在細(xì)胞和組織中扮演著重要角色，通過(guò)TFR1的調(diào)節(jié)來(lái)平衡細(xì)胞內(nèi)鐵含量，維持人體鐵穩(wěn)態(tài)是保證人體各項(xiàng)生理機(jī)能正常運(yùn)作的必要條件 [10-12]。
圖2. Tf-TFR1系統(tǒng)平衡細(xì)胞內(nèi)鐵含量 [2]
2. TFR1相關(guān)的調(diào)控機(jī)制
TFR1是細(xì)胞最重要的鐵元素?cái)z取因子。TFR1表達(dá)量下降或異常會(huì)導(dǎo)致細(xì)胞缺鐵，而過(guò)多的鐵則可能催化活性氧（ROSs）并損傷生物大分子。為了確保充足的鐵元素同時(shí)避免其毒性，細(xì)胞已經(jīng)發(fā)展出多種機(jī)制來(lái)調(diào)控TFR1表達(dá)水平。盡管TFR1異常表達(dá)在多種疾病中發(fā)揮作用，但其分子機(jī)制和作用仍未完全明確。因此，還需要更深入地研究和探索。
TFR1的表達(dá)受多種刺激條件調(diào)控。在轉(zhuǎn)錄水平中，當(dāng)細(xì)胞發(fā)生缺氧時(shí)，缺氧誘導(dǎo)因子（HIF）和其他轉(zhuǎn)錄因子如c-Myc、GATA1、Ets-1以及促紅細(xì)胞生成素Stat5可以促進(jìn)其轉(zhuǎn)錄。TFR1的轉(zhuǎn)錄后水平主要由IRP1和IRP2調(diào)控，它們與TFR1 mRNA中的IRE結(jié)合來(lái)影響基因表達(dá) [13-15]。
在翻譯后水平，CD133（PROM1）是TFR1轉(zhuǎn)運(yùn)鐵元素過(guò)程中的負(fù)調(diào)節(jié)因子，同時(shí)EGF受體、c-Abl分子和MARCH8分子可能也參與其中。如下圖所示，一項(xiàng)研究揭示FLCN有可能在翻譯、或者翻譯后水平調(diào)控TFR1的表達(dá)，即Tf-TFR1復(fù)合物可與含有Rab11蛋白的循環(huán)內(nèi)體相結(jié)合，回到細(xì)胞膜上（圖3）[13-17]。
TFR1在疾病中發(fā)揮調(diào)控作用。例如，在膠質(zhì)瘤中，TFR1通過(guò)炎癥反應(yīng)，細(xì)胞周期，DNA損失及DNA甲基化等機(jī)制參與膠質(zhì)瘤的發(fā)生發(fā)展。此外，PD1信號(hào)，如IL17，IL18，NF-kβ，FOXM1，F(xiàn)OCAL及JAK-STAT信號(hào)可能是TFR1調(diào)控的關(guān)鍵信號(hào)通路 [18-20]。在神經(jīng)干細(xì)胞中敲除TFR1發(fā)現(xiàn)，條件性敲除小鼠有癲癇的癥狀。并且在此研究中還發(fā)現(xiàn)GluA2在海馬神經(jīng)元突觸上表達(dá)增加，其中突觸前的神經(jīng)遞質(zhì)釋放能力下降，突觸后長(zhǎng)時(shí)程增強(qiáng)（LTP）受到一定的抑制 [21-23]。
圖3. FLCN通過(guò)Rab11A調(diào)控Tf-TFR1蛋白的回收運(yùn)輸 [17]
3. TFR1在腫瘤、神經(jīng)退行性等疾病中的作用
正常人體鐵代謝處于平衡狀態(tài)，當(dāng)其中的某一調(diào)控環(huán)節(jié)出現(xiàn)異常導(dǎo)致平衡被打破時(shí)，會(huì)影響細(xì)胞內(nèi)自由基形成并加速氧化應(yīng)激反應(yīng)進(jìn)展，同時(shí)也可導(dǎo)致腫瘤發(fā)生和發(fā)展。TFR1作為細(xì)胞攝取鐵元素過(guò)程中最重要的調(diào)控受體，在多種疾病的發(fā)生發(fā)展過(guò)程中起到重要作用。
3.1 TFR1和腫瘤
現(xiàn)有研究表明TFR1在甲狀腺癌 [24]、食管鱗狀細(xì)胞癌 [25]、乳腺癌 [26]、肝癌 [27]、結(jié)腸癌 [28]、白血病 [29]、肺癌 [30]、胰腺癌 [31]、鼻咽癌 [31]等惡性腫瘤中顯著表達(dá)。但在部分惡性腫瘤中，TFR1表達(dá)情況尚不明確，其中包括：前列腺癌、睪丸癌等。例如，在肝癌中，TFR1在肝癌中的表達(dá)與甲胎蛋白和血清凝血酶原的濃度有關(guān) [27]；在乳腺癌中，敲降IRP2表達(dá)，可提高鐵蛋白重鏈的表達(dá)，并下調(diào)TFR1蛋白表達(dá)，從而抑制乳腺癌細(xì)胞的生長(zhǎng) [26, 32]；在結(jié)腸癌中，TFR1的高表達(dá)可激活I(lǐng)L-6/IL-11-Stat3信號(hào)通路，促進(jìn)結(jié)腸上皮細(xì)胞的增殖和凋亡，從而加重結(jié)腸黏膜的損傷并導(dǎo)致結(jié)腸癌的發(fā)生 [28, 33]。
3.2 TFR1和神經(jīng)退行性疾病
鐵代謝的紊亂是引發(fā)神經(jīng)退行性疾病的病理生理機(jī)制之一。鐵在大腦中的蓄積，與阿爾茨海默病、帕金森病、肌萎縮側(cè)索硬化等神經(jīng)退行性疾病有關(guān) [34]。阿爾茨海默病是最常見(jiàn)神經(jīng)退行性疾病之一，其主要以淀粉樣斑塊的積聚以及某些神經(jīng)元的丟失為發(fā)病特征。有研究表明，抑制阿爾茲海默模型小鼠大腦顳葉皮層中的鐵攝取蛋白TFR1、TF以及DMT1的表達(dá)，可有效緩解鐵過(guò)載狀態(tài) [35-36]。
3.3 TFR1和貧血
TFR1與Tf復(fù)合物的結(jié)合，對(duì)紅細(xì)胞生成過(guò)程中細(xì)胞獲取鐵元素有著重要意義。當(dāng)人體內(nèi)發(fā)生缺鐵或者紅細(xì)胞生成增多時(shí)，TFR1的表達(dá)將被反應(yīng)性上調(diào)。臨床研究證實(shí)，地中海貧血小鼠體內(nèi)的溶性轉(zhuǎn)鐵蛋白受體（sTFR1）和TF的水平都顯著高于正常值。進(jìn)一步研究揭示，TFR1在β-地中海紅系前體細(xì)胞中異常高表達(dá)，降低TFR1的表達(dá)可有效調(diào)節(jié)貧血小鼠中無(wú)效紅細(xì)胞的生成并改善小鼠的貧血以及鐵過(guò)載情況 [7, 37]。
3.4 TFR1和其它疾病
TFR1不僅參與細(xì)胞鐵離子運(yùn)輸，有研究提示TFR1還可作為多種病毒受體介導(dǎo)HCV與宿主細(xì)胞膜融合，在HCV入胞過(guò)程中發(fā)揮重要作用。丙型肝炎病毒（HCV）是導(dǎo)致慢性化肝炎、原發(fā)性肝癌的主要病原體。因此，TFR1作為HCV抗病毒靶點(diǎn)的潛在可能性值得關(guān)注 [38-40]。在神經(jīng)元中，研究發(fā)現(xiàn)TFR1對(duì)mGlul的轉(zhuǎn)運(yùn)起到重要的調(diào)節(jié)作用，并且可能參與了mGlul信號(hào)通路，且對(duì)小腦的運(yùn)動(dòng)協(xié)調(diào)能力起到影響 [41-42]。
4. TFR1的臨床研究進(jìn)展
目前已有多款針對(duì)轉(zhuǎn)鐵蛋白受體1(TFR1)的臨床藥物正在研發(fā)中，藥物類型涵蓋抗體核酸偶聯(lián)藥物、雙體、單體、抗體融合蛋白、ADC藥物等；適應(yīng)癥涉及非小細(xì)胞肺癌、食管癌、黏多醣貯積癥型、肌強(qiáng)直性營(yíng)養(yǎng)不良、阿爾茨海默癥、杜氏肌營(yíng)養(yǎng)不良癥等。其中，JCR Pharmaceuticals Co., Ltd.的Pabinafusp Alfa，一款靶向IDS和TfR1的抗體融合蛋白已于2021年日本上市。近年來(lái)，基于TFR1的靶向治療策略在不斷發(fā)展。有研究利用TFR1提高抗體跨越血腦屏障的轉(zhuǎn)運(yùn)能力，并與抗β-淀粉樣肽單抗相結(jié)合形成特異性復(fù)合抗體，以提高阿爾茨海默病患者的治療效果 [43-44]。
同時(shí)，抗TFRC的抗體JST-TFR09和抗TFRC單克隆抗體A24分別可抑制腫瘤細(xì)胞對(duì)鐵元素的攝取，以及誘導(dǎo)T系細(xì)胞白血病中惡性細(xì)胞的凋亡 [45-46]。這些研究提示，TFR1可成為有效的靶標(biāo)分子參與到多種疾病的臨床治療。未來(lái)，隨著TFR1相關(guān)研究的不斷深入和完善，有望為患者提供更加精準(zhǔn)、有效的治療，為他們帶來(lái)更多的獲益和新希望。
5. 華美生物TFR1相關(guān)產(chǎn)品
● TFR1重組蛋白
Recombinant Human Transferrin receptor protein 1(TFRC),partial (Active) (Code: CSB-MP3648HU)
High specificity was validated by SDS-PAGE. SDS-PAGE (reduced) with 5% enrichment gel and 15% separation gel.
Immobilized Human TFRC at 2μg/mL can bind Anti-TFRC recombinant antibody (CSB-RA023441MA1HU), the EC50 is 3.305-8.220 ng/mL.
● TFR1抗體
| 產(chǎn)品名稱 | 適應(yīng)種屬 | 應(yīng)用 | 貨號(hào) |
|---|---|---|---|
| TFRC Recombinant Monoclonal Antibody | Human | ELISA | CSB-RA023441MA1HU |
| TFRC Antibody | Human | ELISA, IHC, IF | CSB-PA07219A0Rb |
| TFRC Antibody | Human, Mouse | ELISA, WB, IHC | CSB-PA001477 |
| TFRC Antibody | Human | ELISA, WB | CSB-PA005607 |
| Phospho-TFRC (S24) Antibody | Human, Mouse | ELISA, WB, IHC | CSB-PA010092 |
| TFRC Antibody | Human, Mouse, Rat | ELISA, WB, IHC | CSB-PA023441GA01HU |
| TFRC Antibody | Human, Mouse, Rat | ELISA, WB, IHC | CSB-PA104885 |
| TFRC Antibody | Human, Mouse, Rat | ELISA, WB, IHC | CSB-PA834425 |
● TFR1 ELISA試劑盒
| 產(chǎn)品名稱 | 檢測(cè)樣本 | 檢測(cè)范圍 | 貨號(hào) |
|---|---|---|---|
| Mouse transferrin receptor,TFR ELISA Kit | serum, plasma, tissue homogenates | 0.625 ng/mL-40 ng/mL | CSB-E08389m |
| Human soluble transferrin receptor,sTfR ELISA Kit | serum, plasma | Request Information | CSB-E09100h |
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