TRIM蛋白家族調(diào)節(jié)NF-κB信號(hào)通路的研究進(jìn)展①

金 爭 李 冬 閆東梅 朱 迅

(吉林大學(xué)基礎(chǔ)醫(yī)學(xué)院免疫學(xué)系，長春130021)

·專題綜述·

TRIM蛋白家族調(diào)節(jié)NF-κB信號(hào)通路的研究進(jìn)展①

金 爭 李 冬 閆東梅 朱 迅

(吉林大學(xué)基礎(chǔ)醫(yī)學(xué)院免疫學(xué)系，長春130021)

核因子-κB(Nuclear factor-kappa B，NF-κB)作為重要的核轉(zhuǎn)錄因子參與調(diào)節(jié)機(jī)體的免疫應(yīng)答，一旦其調(diào)節(jié)發(fā)生異常將會(huì)導(dǎo)致免疫疾病、神經(jīng)退行性病變、新陳代謝疾病、腫瘤等。磷酸化、泛素化等轉(zhuǎn)錄后修飾可調(diào)節(jié)NF-κB信號(hào)通路。E3泛素連接酶在泛素化的過程中起重要作用[1]。TRIM(Tripartite motif)蛋白是E3泛素連接酶中RING家族成員，由RING、B-Box、Coil-coiled和C端結(jié)構(gòu)域構(gòu)成[2]。已有研究證明在感染等病理?xiàng)l件下，TRIM蛋白能調(diào)節(jié)固有免疫應(yīng)答[3]。最近研究表明，TRIM作為泛素連接酶調(diào)節(jié)NF-κB信號(hào)通路[4]。我們將對TRIM家族蛋白調(diào)節(jié)NF-κB信號(hào)通路及其在免疫疾病中的研究進(jìn)展做簡要綜述。

1 TRIM蛋白家族

近年來，隨著對TRIM蛋白家族研究的不斷深入，TRIM蛋白的重要性也越來越突出。TRIM蛋白屬于E3泛素連接酶中RING家族，所有的哺乳動(dòng)物都表達(dá)TRIM蛋白，人類大約表達(dá)60種TRIM蛋白及8種TRIM樣蛋白，小鼠表達(dá)64種TRIM蛋白，蠕蟲和蒼蠅只表達(dá)10～20種TRIM蛋白[3]。TRIM蛋白家族最顯著的特點(diǎn)是具有三結(jié)構(gòu)域(Tripartite-motif domain)結(jié)構(gòu)，從N端到C端依次是一個(gè)鋅指結(jié)構(gòu)域(RING domain)、一個(gè)或兩個(gè)B-Box結(jié)構(gòu)域(B-Box domain)、一個(gè)卷曲螺旋結(jié)構(gòu)域(Coiled-coil domain)和C端的非特異性的結(jié)構(gòu)域(C-terminal domain)，故TRIM蛋白也被稱為RBCC蛋白[5]。大多數(shù)研究認(rèn)為，RING結(jié)構(gòu)域能特異性結(jié)合E2泛素結(jié)合酶，從而發(fā)揮E3泛素連接酶的作用[6,7]。也有研究表明，RING結(jié)構(gòu)域在蛋白相互作用中也有一定作用，可能參與NF-κB信號(hào)通路的調(diào)節(jié)[6,8]?，F(xiàn)有的研究對B-Box結(jié)構(gòu)與功能的了解十分有限，TRIM蛋白中的B-Box被證實(shí)與自身免疫疾病有關(guān)。B-Box在結(jié)構(gòu)上與RING類似，有人認(rèn)為它也可以作為E2的結(jié)合位點(diǎn)發(fā)揮E3泛素連接酶的作用，如TRIM16缺少RING結(jié)構(gòu)域，在體外實(shí)驗(yàn)中仍發(fā)揮E3泛素連接酶的作用[9]。Coiled-coil結(jié)構(gòu)域主要參與同源二聚體的相互作用和低聚反應(yīng)[10-12]，促進(jìn)大分子復(fù)合物的形成，影響蛋白的亞細(xì)胞定位[12]，并且異源二聚體的形成使卷曲螺旋結(jié)構(gòu)域的功能更加多元化[5]。

TRIM蛋白有多種表達(dá)形式，細(xì)胞質(zhì)、細(xì)胞核中均有表達(dá)。表達(dá)的部位大多數(shù)與明確定義的亞細(xì)胞結(jié)構(gòu)如內(nèi)質(zhì)網(wǎng)、高爾基體無關(guān)，而是表達(dá)于其他亞細(xì)胞區(qū)域[12,13]，如TRIM19表達(dá)于核體，參與轉(zhuǎn)錄的調(diào)節(jié)[14,15]。

TRIM蛋白因有RING結(jié)構(gòu)而被歸為E3泛素連接酶的RING家族，在泛素化中發(fā)揮作用[3]。泛素化是泛素分子以共價(jià)鍵結(jié)合特異性目的蛋白的賴氨酸殘基，發(fā)生轉(zhuǎn)錄后修飾的過程[16]。泛素活化酶(E1)、泛素交聯(lián)酶(E2)、泛素連接酶(E3)是泛素化的重要組成部分，其中E3的作用是將E2與目的蛋白連接[16]。最初，泛素化被認(rèn)為是蛋白酶降解的一種機(jī)制，隨著研究的深入，人們發(fā)現(xiàn)泛素化也可以調(diào)節(jié)其他的細(xì)胞過程，如轉(zhuǎn)錄、蛋白質(zhì)的運(yùn)輸[16]。泛素化參與了許多病理過程，如腫瘤、炎癥及自身免疫紊亂[17-19]。TRIM蛋白作為泛素連接酶參與抗病毒和調(diào)節(jié)免疫相關(guān)信號(hào)通路的過程。但是，TRIM蛋白家族所有成員是否都具有泛素連接酶作用并未得到證實(shí)[20]。

2 TRIM家族蛋白對NF-κB信號(hào)通路的調(diào)節(jié)

NF-κB信號(hào)通路和TRIM蛋白之間存在相互作用。有研究表明，NF-κB信號(hào)通路能調(diào)節(jié)TRIM家族蛋白的表達(dá)，TRIM家族蛋白也能雙向調(diào)節(jié)NF-κB信號(hào)通路。如腫瘤壞死因子(Tumor necrosis factor alpha，TNF-α)介導(dǎo)的NF-κB信號(hào)通路活化能上調(diào)TRIM9、TRIM21、TRIM62的表達(dá)，而這些TRIM蛋白反過來又可對NF-κB信號(hào)通路產(chǎn)生正向或負(fù)向調(diào)節(jié)[2,21,22]，見表1。

3 TRIM家族蛋白調(diào)節(jié)NF-κB信號(hào)通路的機(jī)制

NF-κB是一個(gè)轉(zhuǎn)錄因子蛋白家族，包括5個(gè)亞單位：RelA(p65)、RelB、c-Rel、p50和p52。NF-κB分為經(jīng)典通路和非經(jīng)典通路兩大部分，二者既相互影響又相互獨(dú)立。經(jīng)典通路中，TNF-α、脂多糖(LPS)、IL-1等通過受體將信號(hào)傳遞至細(xì)胞內(nèi)，接頭蛋白MyD88(Myeloid differentiation primary response gene 88)招募TRAF6(TNF receptor associated factor 6)，后者通過自身泛素化形成一個(gè)包括在內(nèi)IKK(Inhibitor of nuclear factor kappa-B kinase)復(fù)合物激酶(TAK1、TAB2/3)的復(fù)合物，復(fù)合物中的TAK1能激活I(lǐng)KK復(fù)合物(IKK-α、IKK-β、NEMO)，IKK復(fù)合物被激活后，作用于NF-κB抑制物IκBα(Inhibitor of NF-κB)，使之磷酸化，進(jìn)而發(fā)生泛素化修飾并通過蛋白酶體通路降解，從而釋放核因子p65/RelA和p50/52復(fù)合物入核，結(jié)合相應(yīng)的DNA位點(diǎn)，調(diào)控相關(guān)基因轉(zhuǎn)錄[23]。在非經(jīng)典通路中，CD40L(腫瘤壞死因子相關(guān)激活蛋白)、B細(xì)胞激活因子(BAFF/Blys)、LT-β(Lymphotoxin-β)等刺激下，TRAF3、TRAF2被招募與受體形成復(fù)合物，TRAF2的RING結(jié)構(gòu)使TRAF3發(fā)生多聚泛素化，復(fù)合物降解，NIK(NF-κB-inducing kinase)被激活，促進(jìn)IKK-α的磷酸化，被激活的NIK和IKK-α 一起磷酸化p100并加工成p52，使p52/RelB復(fù)合物活化，啟動(dòng)NF-κB非經(jīng)典通路[24,25]。近年來大量的研究證實(shí)，RIG-Ⅰ(Retinoic acid inducible gene Ⅰ)也可激活NF-κB信號(hào)通路。RIG-Ⅰ能夠識(shí)別病毒的RNA組分，并通過自身的CARD(Anino-terminal caspase recruitment domain)與下游信號(hào)分子MAVS(Mitochondrial antiviral signaling proteinprovided)的CARD相互作用來傳遞信號(hào)，MAVS含有兩個(gè)TRAF6結(jié)合模序,能夠與TRAF6結(jié)合，激活細(xì)胞轉(zhuǎn)錄因子NF-κB，使其進(jìn)入細(xì)胞核內(nèi)，結(jié)合相應(yīng)的DNA序列，增強(qiáng)機(jī)體抵抗病毒的能力[26]。TRIF(TIR-domain-containing adaptor inducing interferon-β)及RIP1(Receptor-interacting protein 1)也可介導(dǎo)NF-κB信號(hào)通路。在LPS等刺激下，Toll樣受體招募TRIF，RIP1結(jié)合于TRIF C端，并通過同型DD結(jié)構(gòu)域與TRADD(TNF receptor associated death domain protein)結(jié)合，TRADD連接E3泛素連接酶，使RIP1發(fā)生K63位多聚泛素化修飾，泛素化的RIP1被TAB2/TAB3識(shí)別，并由此激活TAK1，從而激活NF-κB信號(hào)通路[27]。TRIM家族蛋白可結(jié)合以上通路中的多個(gè)靶點(diǎn)，正向或負(fù)向調(diào)節(jié)NF-κB信號(hào)通路，從而調(diào)節(jié)各種生理或病理活動(dòng)，見圖1。

表1 TRIM家族蛋白對NF-κB信號(hào)通路的調(diào)節(jié)

圖1 NF-κB信號(hào)通路Fig.1 NF-κB signaling pathways

3.1TRIM家族蛋白對TRAF6調(diào)節(jié) TRAF6蛋白屬于TRAF家族，能介導(dǎo)多種信號(hào)通路，其中包括NF-κB信號(hào)通路。在LPS等刺激物激活的NF-κB信號(hào)通路中，TRAF6通過自身泛素化而活化IKK激酶TAK1，調(diào)節(jié)NF-κB信號(hào)通路[28]。TRIM12c是TRIM5樣蛋白，在巨噬細(xì)胞和樹突狀細(xì)胞中，能結(jié)合TRAF6，促進(jìn)其泛素化，激活TAK1，正向調(diào)節(jié)NF-κB信號(hào)通路[29]。人巨細(xì)胞病毒與TRIM23結(jié)合，后者促進(jìn) TRAF6的自身泛素化，從而實(shí)現(xiàn)對 NF-κB信號(hào)通路的正向調(diào)節(jié)[30]。TFG(TPK-fused gene)能作用于TRAF6，激活NF-κB。在TLR3(Toll-like receptor 3)介導(dǎo)的信號(hào)通路中，TRIM68通過結(jié)合TFG抑制TRAF6激活，負(fù)向調(diào)節(jié)NF-κB信號(hào)通路[31]。在巨噬細(xì)胞中，TRIM38結(jié)合TRAF6，對其進(jìn)行K48位的多聚泛素化修飾，促進(jìn)TRAF6蛋白酶體通路的降解，抑制TLR(Toll-like receptor)介導(dǎo)的NF-κB信號(hào)通路[32]。

3.2TRIM家族蛋白對IKK復(fù)合物激酶的調(diào)節(jié) IKK復(fù)合物激酶(TAK1、TAB2/3)對IKK復(fù)合物的激活至關(guān)重要。在IL-1β、TNF-α等介導(dǎo)的NF-κB信號(hào)通路中，TRIM8結(jié)合TAK1，介導(dǎo)其K63位的多聚泛素化，激活TAK1，正向調(diào)節(jié)NF-κB信號(hào)通路[33]。TRIM30α結(jié)合TAB2-TAB3-TAK1復(fù)合物，促進(jìn)TAB2-TAB3的降解，抑制TLRs介導(dǎo)的NF-κB信號(hào)通路的激活[34]。TRIM22能激活人巨噬細(xì)胞中的NF-κB信號(hào)通路，但其機(jī)制不清[35,36]。也有研究發(fā)現(xiàn)TRIM22通過RING結(jié)構(gòu)域降解TAB2，負(fù)向調(diào)節(jié)TRAF6介導(dǎo)的NF-κB信號(hào)通路[36]。最近研究顯示，TRIM38作為E3泛素連接酶促進(jìn)TAB2/3的溶酶體降解，抑制TNF-α和IL-1β介導(dǎo)的NF-κB信號(hào)通路[37]。

3.3TRIM家族蛋白對IKK復(fù)合物的調(diào)節(jié) IKK復(fù)合物能激活I(lǐng)κB，使其降解，解除IκB對NF-κB的抑制作用。TRIM23不僅能通過TRAF6調(diào)節(jié)NF-κB信號(hào)通路，還可通過調(diào)節(jié)IKK復(fù)合物影響NF-κB信號(hào)通路。有研究證明在抗病毒的免疫應(yīng)答中，TRIM23作為E3泛素連接酶介導(dǎo)NEMO(IKKγ)的K27位多聚泛素化，激活下游通路，正向調(diào)節(jié)NF-κB通路[38]。TRIM13是內(nèi)質(zhì)網(wǎng)上的E3泛素連接酶，能通過抑制NEMO泛素化，抑制NF-κB信號(hào)通路[39]。NEDD8(Neural precursor cell-expressed developm-entally downregulated 8)分子是一類結(jié)構(gòu)上與泛素相似的分子，參與蛋白質(zhì)翻譯后修飾，這一過程被稱為Neddylation。在消化道腫瘤的研究中，NEDD8能特異性結(jié)合并修飾NEMO，抑制NEMO的活化，從而抑制NF-κB信號(hào)通路。TRIM40結(jié)合NEDD8，增強(qiáng)NEDD8對NEMO的抑制作用，從而負(fù)向調(diào)節(jié)NF-κB信號(hào)通路。進(jìn)一步研究發(fā)現(xiàn)，TRIM40在正常胃腸道上皮細(xì)胞中高表達(dá)，在胃腸道的炎癥和腫瘤中低表達(dá)[40]。TRIM68不僅能通過結(jié)合TFG抑制TRAF6激活，也可通過結(jié)合TFG 抑制NEMO的激活，從而抑制NF-κB信號(hào)通路[31]。在感染HTLV1(Human T-lymphotropic virus 1)的細(xì)胞中，Tax蛋白使IKK-β持續(xù)磷酸化，激活NF-κB信號(hào)通路，促進(jìn)細(xì)胞增殖。TRIM21抑制Tax蛋白的表達(dá)，介導(dǎo)寡聚泛素化使IKK-β發(fā)生自噬降解，從而抑制NF-κB信號(hào)通路[41]。TRIM27結(jié)合IKK復(fù)合物，抑制后者的激活，負(fù)向調(diào)節(jié)TNF、IL-1、TLR3及病毒感染激活的NF-κB信號(hào)通路[42]。

3.4TRIM家族蛋白對IκB的調(diào)節(jié) 在靜息狀態(tài)下，IκB與NF-κB結(jié)合，抑制NF-κB信號(hào)通路。TRIM20，也稱為MEFV(Mediterranean fever)蛋白，是Caspase-1的靶蛋白，其N端結(jié)構(gòu)域結(jié)合IκBα，促進(jìn)鈣蛋白酶介導(dǎo)的IκBα的降解，從而正向調(diào)節(jié)NF-κB信號(hào)通路[43]。TRIM9結(jié)合β-TrCP(E3泛素連接酶復(fù)合物)，阻止β-TrCP與IκBα結(jié)合，并防止β-TrCP降解，負(fù)向調(diào)節(jié)NF-κB信號(hào)通路[44]。

3.5TRIM家族蛋白對NF-κB轉(zhuǎn)錄的調(diào)節(jié) TRIM家族蛋白對NF-κB也有一定的調(diào)節(jié)作用。TRIM19，又稱PML(Promyelocytic leukemia)蛋白，其C端結(jié)構(gòu)域能結(jié)合RelA和p65，阻止RelA和p65與同源增強(qiáng)子的結(jié)合，抑制NF-κB信號(hào)通路[45]。PIAS3(Protein inhibitor of activated STAT 3)可作為SUMO(Small ubiquitin-like modifier)的E3連接酶，通過加強(qiáng)SUMO與NF-κB的結(jié)合促進(jìn)NF-κB的SUMO化修飾，使p65從細(xì)胞核轉(zhuǎn)移至細(xì)胞質(zhì)，抑制NF-κB信號(hào)通路。TRIM8不僅能通過TAK1激活NF-κB，同時(shí)它也是一個(gè)核蛋白，在核內(nèi)通過抑制PIAS3，促進(jìn)p65從細(xì)胞質(zhì)轉(zhuǎn)移至細(xì)胞核，正向調(diào)節(jié)NF-κB信號(hào)通路[46]。TRIM20的N端結(jié)構(gòu)域不僅能結(jié)合IκBα，還能結(jié)合p65，促進(jìn)p65入核，正向調(diào)節(jié)NF-κB信號(hào)通路[43]。

3.6TRIM家族蛋白對NF-κB信號(hào)通路其他分子的調(diào)節(jié) 除上述分子外，TRIM家族蛋白還通過其他分子調(diào)節(jié)NF-κB信號(hào)通路。仙人掌素(Cactin)是NF-κB的抑制劑，在TNF-α介導(dǎo)的NF-κB信號(hào)通路中，TRIM39通過增強(qiáng)仙人掌素的穩(wěn)定性，間接負(fù)向調(diào)節(jié)NF-κB信號(hào)通路[47]。非小細(xì)胞肺癌中，TRIM44通過上調(diào)CXCL16(C-X-C chemokine ligand 16)和MMP9(Matrix metallopeptidase 9)激活NF-κB信號(hào)通路，促進(jìn)非小細(xì)胞肺癌的發(fā)展，但其機(jī)制不清[48]。另有研究表明，在抗病毒感染中，TRIM44通過B-Box結(jié)合MAVS，阻止MAVS的K48位多聚泛素化修飾，避免其降解，增強(qiáng)了穩(wěn)定性，正向調(diào)節(jié)NF-κB信號(hào)通路[49]。ECSIT(Evolutionarily conserved signaling intermediate in Toll pathways)是RLR信號(hào)通路中的關(guān)鍵分子，TRIM59結(jié)合并抑制ECSIT的激活，抑制RIG-Ⅰ介導(dǎo)的NF-κB信號(hào)通路[50]。 TRIM25羧基末端的SYBR結(jié)構(gòu)域結(jié)合于RIG-Ⅰ N端的CARD結(jié)構(gòu)域，促進(jìn)了CARD結(jié)構(gòu)域K63位的泛素化修飾，正向調(diào)節(jié)NF-κB信號(hào)通路[51]。通過調(diào)節(jié)RIG-Ⅰ多聚泛素化正向調(diào)節(jié)NF-κB信號(hào)通路。TRIM4也是通過對RIG-Ⅰ進(jìn)行K63位的泛素化修飾，正向調(diào)節(jié)NF-κB信號(hào)通路[52]。TRIM1、TRIM62和TRIM32正向調(diào)節(jié)NF-κB信號(hào)通路，TRIM45負(fù)向調(diào)節(jié)NF-κB信號(hào)通路，但其機(jī)制尚不十分明確[53，54]。以上研究表明，在生理或病理情況下，TRIM家族蛋白對NF-κB信號(hào)通路的調(diào)節(jié)具有重要意義。

4 展望

TRIM家族蛋白對NF-κB信號(hào)通路的調(diào)節(jié)在炎癥、細(xì)胞信號(hào)通路中起重要作用。對于許多疾病，如腫瘤、炎癥、自身免疫病，NK-κB是有效的藥物作用靶點(diǎn)[55,56]。但是目前針對NF-κB的非選擇性或完全性抑制存在一定的局限性及副作用。非甾體類抗炎藥最早應(yīng)用于炎癥的治療中，阿司匹林和水楊酸鈉通過作用于IKK-β上三磷酸腺苷(ATP)的結(jié)合位點(diǎn)抑制NF-κB信號(hào)通路[57]，但其可引發(fā)嚴(yán)重的超敏反應(yīng)[58]。糖皮質(zhì)激素類藥物用于過敏及自身免疫病，是利用其對NF-κB信號(hào)通路的抑制作用[59]，而隨之而來的是肝、肌肉等葡萄糖不耐受疾病[60]。硼替佐米是蛋白酶體抑制劑，能阻斷IκBα的降解，抑制NF-κB，目前已成功應(yīng)用于血液腫瘤的治療[61,62]，但在實(shí)體瘤中應(yīng)用十分有限。TRIM家族蛋白能適度調(diào)節(jié)NF-κB信號(hào)通路，在特定的生理病理?xiàng)l件下，可以形成高級(jí)結(jié)構(gòu)作為信號(hào)轉(zhuǎn)導(dǎo)體，因此可以作為一個(gè)有效的作用靶點(diǎn)，為臨床許多與NF-κB信號(hào)通路異常有關(guān)疾病的治療提供新思路。

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[收稿2017-10-27 修回2017-12-20]

(編輯 許四平)

10.3969/j.issn.1000-484X.2017.06.025

①本文受國家自然科學(xué)基金(81571530)資助。

金 爭(1992年-)，女，在讀碩士，主要從事腫瘤免疫相關(guān)研究，E-mail:jzjinzhengjz@163.com。

及指導(dǎo)教師：閆東梅(1978年-)，女，博士，副教授，碩士生導(dǎo)師，主要從事細(xì)胞免疫相關(guān)研究，E-mail:dmyan@jlu.edu.cn。 朱 迅(1958年-)，男，博士，教授，博士生導(dǎo)師，主要從事分子免疫與腫瘤免疫相關(guān)研究，E-mail:zxunzhux@vip.sohu.com。

R292.9

A

1000-484X(2017)06-0924-06