鄭 航,孫英杰,張 頻,丁 鏟
(1.吉林農業(yè)大學動物科學技術學院,長春 130118;2.中國農業(yè)科學院上海獸醫(yī)研究所,上海 200241;3. 山東農業(yè)大學動物科技學院,泰安 271018)
MAVS介導的抗病毒天然免疫信號通路的調控
鄭 航1,孫英杰2,張 頻1,丁 鏟2
(1.吉林農業(yè)大學動物科學技術學院,長春 130118;2.中國農業(yè)科學院上海獸醫(yī)研究所,上海 200241;3. 山東農業(yè)大學動物科技學院,泰安 271018)
先天性免疫通路作為抵御入侵的病原微生物第一道屏障,在宿主抗病毒反應中發(fā)揮重要的作用。細胞質中最重要的識別病毒RNA的模式識別受體是維甲酸誘導基因蛋白I和黑色素瘤分化相關基因5,它們有著相同的下游信號接頭分子線粒體抗病毒信號蛋白(mitochondrial antiviral-signaling protein, MAVS),MAVS在介導的先天性免疫中起中樞作用。MAVS介導的信號通路的激活是重要的抗病毒反應,但在長期的共存過程中,病毒進化出一系列拮抗MAVS的機制。同時,在靜息狀態(tài)下,為了防止過度免疫反應,細胞還具備一系列調控MAVS的機制。MAVS的精細調控對于行使細胞功能和發(fā)揮抗病毒反應至關重要。本文簡單介紹了MAVS的結構和功能,總結了細胞對MAVS的轉錄和翻譯后調控,最后闡述了病毒如何通過調控MAVS拮抗宿主先天性免疫,為細胞的免疫調節(jié)和控制病毒感染提供新的思路。
天然免疫;線粒體抗病毒信號蛋白;病原體;宿主
病毒感染細胞能夠激活一系列先天性抗病毒反應,其中最重要的一種先天性抗病毒機制是通過模式識別受體(pattern recognition recetproreceptor,PRRs)識別病毒從而誘導產生干擾素(interferon,IFN)和促炎性因子(proinflammatory cytokines),抑制病毒復制。而在所有保守的模式識別受體中,維甲酸誘導基因蛋白I(retinoic acid-inducible gene 1,RIG-I)和黑色素瘤分化相關基因5(melanoma differentiation-associated protein 5,MDA5)是最重要的細胞質模式識別受體,在病毒感染時識別病毒RNA,激活下游一系列抗病毒信號通路,誘導表達I型干擾素和其他的促炎因子[1,2]。RIG-I和MDA5是相似的兩種受體,識別不同種類的病毒RNA,它們有著相同的下游信號接頭分子線粒體抗病毒信號蛋白(Mitochondrial antiviral-signaling protein,MAVS,又稱IPS-1、VISA、CARDIF)[3,4]。RIG-I、MDA5通過N端串聯的caspase招募結構域(amino-terminal caspase recruitment domain,CARD)與MAVS的N端 CARD結構域互作,激活下游NF-кB(nuclear factor κB)和IRF3/7(interferon regulatory factors 3/7)相關信號通路,并誘導干擾素的表達,參與先天性抗病毒反應[5,6]。MAVS在介導的先天性免疫中起中樞作用,因此MAVS介導的信號通路的激活是重要的抗病毒反應,但在長期的共存過程中,病毒有了一系列拮抗MAVS的機制。同時,在靜息狀態(tài)下,為了防止過度免疫反應,細胞還具備一系列調控MAVS的機制。MAVS的精細調控對于行使細胞功能和發(fā)揮抗病毒反應至關重要[7]。
M A V S是由細胞核基因組編碼的,并在不同組織和細胞中均有表達的蛋白[5]。MAVS由N端的C A R D結構域,富含脯氨酸結構域(proline-rich domain,PRD)和C端的跨膜結構域 (transmembrane domain,TM)組成[8]。MAVS在所介導的先天性抗病毒反應中起中樞性的作用,以RIG-I信號通路為例,E3泛素連接酶Riplet和TRIM25在其識別RNA和激活的過程中發(fā)揮關鍵作用,RIG-I被Riplet和TRIM25(tripartite motifcontaining protein 25)介導的K63泛素化修飾后發(fā)生活化,RIG-I多聚化后和TRIM25及分子伴侶14-3-3ε形成復合物,這種復合物被稱之為“轉位子(translocon)”,轉位子從細胞質轉運至細胞內膜,例如線粒體相關膜(mitochondrion-associated membrane, MAM)和MAVS結合[9]。MAVS的N端的CARD區(qū)域與胞質中與RIG-I的2CARD結構域結合,隨后激活下游的兩種細胞質蛋白激酶復合物,一種包括“非經典”IKK-相關激酶TBK1(TANK-binding kinase 1)或IKK-i/ε(inducible I B kinase)和一系列接頭蛋白例如TANK(TRAF family member associated NF- B activator)、NAP1(NAK-associated protein 1)和NEMO(NF- B Essential Modulator)。這種TBK1復合物負責激活轉錄因子IRF3和IRF7的磷酸化和二聚化,IRF3和IRF7轉位至細胞核中,與干擾素刺激反應元件(IFN-stimulated response elements,ISREs)結合,誘導I型IFN基因和一系列干擾素誘導基因(ISG)的表達。另一種激酶復合物包括IKKa、IKKb和NEMO,這種IKK復合物激活NF-κB,促進下游促炎性細胞因子的表達,參與先天性抗病毒反應[5,10]。
MAVS是經典的“尾部錨定”膜蛋白,其C端的跨膜結構域(TM)使MAVS錨定在許多細胞器膜表面,例如線粒體、過氧化物酶體以及內質網的亞結構域(MAM)[6]。MAVS不同亞細胞定位的具體機制還未知,據推測MAVS可能通過識別膜上特定的脂質或蛋白而錨定在不同的細胞器膜上,發(fā)揮其抗病毒功能。MAVS的這種膜定位特性對其發(fā)揮抗病毒活性是必須的,去除MAVS跨膜結構域使其喪失抗病毒活性[6]。在表達只含有CARD結構域和TM結構域的MAVS突變體(miniMAVS),仍然可以引起MAVS介導的信號傳導,miniMAVS仍可以保持MAVS線粒體定位、寡聚化、CARD結構域的吸附的功能特性,這種MAVS的解螺旋酶域和C末端結合域(CTD)是識別病毒RNA,激活下游信號通路的必需結構[5]。
2.1 MAVS的轉錄和轉錄后調控 MAVS不屬于干擾素刺激基因,其表達不直接受干擾素(IFN)調控,因此與RIG-I等基因不同,MAVS的表達和功能更多受到轉錄、轉錄后和翻譯后的調控。在轉錄水平,MAVS mRNA水平受到活性氧(reactive oxygen species,ROS)介導的負反饋環(huán)的調控[6,11]。MAVS基因還編碼一系列不同的剪切體發(fā)揮負調控MAVS介導的信號通路[12]。而在轉錄后水平,MAVS的翻譯能夠在兩個不同的轉錄起始位點,包括用序列中部的甲硫氨酸起始翻譯[13]。這種MAVS的選擇性翻譯可能由上游開放性讀碼框跳躍介導,導致398個氨基酸的缺失CARD結構域的MAVS的短異構體,這種短異構體被稱之為短MAVS(short-MAVS,sMAVS)。盡管有報道認為sMAVS發(fā)揮負調控抗病毒先天性免疫的作用,但也有報道顯示sMAVS發(fā)揮正向調控抗病毒信號通路[13]。最近的兩篇報道顯示RNA病毒感染后,全長MAVS(FL-MAVS)逐漸降解,但sMAVS量則保持恒定[13,14]。FL-MAVS降解的具體機制是由于其在RNA病毒感染后第7和第10位氨基酸發(fā)生K48多泛素化介導的蛋白酶體降解,但是由于sMAVS缺失FL-MAVS的N端序列,因此不發(fā)生K48泛素化降解。介導MAVS降解的E3連接酶是TRIM25,巧合的是,TRIM25正是介導RIG-I的K63活化的E3連接酶,因此推測RNA病毒感染后,MAVS的位置上與RIG-I轉位子成分TRIM25接近而被泛素化。值得注意的是,由于FL-MAVS的降解先于IRF3的磷酸化,說明這種降解正向調控抗病毒信號[14]。
2.2 MAVS的蛋白水平調控
2.2.1 MAVS翻譯后負調控 MAVS通過翻譯后調控先天性抗病毒反應,其中最重要的負調控機制是對MAVS的賴氨酸位點進行K48泛素化修飾,通過蛋白酶體途徑降解MAVS。例如在病毒感染時,E3泛素連接酶RNF5(ring finger protein 5)與線粒體上的MAVS的C末端的跨膜結構域相結合,RNF5在MAVS的氨基酸K362和K461位點進行K48泛素化修飾,降解MAVS,負調控MAVS介導的I型干擾素生成與細胞抗病毒應答[15];另一種E3泛素連接酶MARCH5的RING結構域與MAVS的CARD域結合,阻止MAVS聚集,促進其通過蛋白酶體途徑降解;MAVS的Lys7和Lys500氨基酸位點是E3連接酶MARCH5泛素化關鍵位點,MARCH5負調控MAVS介導的抗病毒信號通路,防止過度的免疫反應[16]。除此之外,還有許多其他E3泛素連接酶介導了MAVS的K48泛素化降解,例如AIP4[17]、Smurf1[18]等。
除了泛素化降解之外,另一種重要的負調控機制是通過與MAVS互作阻斷其介導的抗病毒信號通路,例如TSPAN6(Tetraspanin-6)在病毒感染時自身發(fā)生賴氨酸K63的泛素化修飾,促進了其與MAVS的結合,TSPAN6 和MAVS的互作干擾了RLR下游分子TRAF3, STING(stimulator of interferon genes)和IRF3招募至MAVS,阻斷了信號轉導分子的裝配[19];E3泛素連接酶RNF125通過泛素調控MDA-5和MAVS的結合,來抑制其下游的信號通路傳導;E3泛素連接酶Triad3A與MAVS的TRAF相互作用結構域(TIM)(氨基酸第143-147位)互作,競爭性結合TRAF3位點,負調控機體天然抗病毒反應[20];MUL1(Mitochondrial E3 ubiquitin protein ligase 1)定位在線粒體外膜上,與MAVS相互作用,并催化RIG-I的SUMO化修飾,抑制RIG-I介導的細胞信號傳導[21]。NOD樣受體NLRX1也位于線粒體上,能夠通過扣留MAVS使其遠離RIG-I來發(fā)揮負調控作用[22]。自噬相關蛋白ATG12-ATG5復合物能通過影響MAVS與RIG-I的結合,來負調控I型干擾素信號通路[23]。而COX5B(Cytochrome c oxidase subunit 5B)也能通過與ATG5的互作負調控MAVS介導的信號通路[24]。
除了以上兩種最重要的負調控途徑之外,還有其他一些其他的非經典的負調控機制,例如蛋白酶體PSMA7(α4)亞基與細胞內的MAVS相互作用介導MAVS被蛋白酶體降解[25]。胰島素受體酪氨酸激酶底物(IRTKS)在細胞核中募集E2連接酶UBC9,它在病毒感染期間易位到細胞質,引起SUMO化的PCBP2蛋白介導MAVS降解[26]。蛋白磷酸激酶PLK1(polo-like kinase 1)磷酸化修飾MAVS,從而抑制MAVS招募信號分子。線粒體蛋白也能調控RLR信號通路[27]。兩個協(xié)同的線粒體蛋白MFN1和MFN2(mitofusin 1 and 2)都可與MAVS相互作用,但是其作用不同。MFN2負調控MAVS介導的通路,MFN1通過影響線粒體動態(tài)變化正調控RLR介導的抗病毒信號通路[28]。除了細胞蛋白之外,miRNA也被報道影響MAVS介導的抗病毒反應,水泡性口炎病毒感染后,內源性的miR-576-3p 通過和STING、MAVS和TRAF3結合,抑制IRF3入核,干擾素水平下降[29]。
2.2.2 MAVS翻譯后正調控 有很多蛋白被發(fā)現通過對MAVS的翻譯后修飾正調控MAVS介導信號傳導通路[30]。其中最重要的正調控機制是對MAVS的賴氨酸位點進行K63泛素化修飾,活化MAVS。例如線粒體接頭蛋白TRIM14與MAVS相互作用,促進了MAVS信號小體(signalosome)組裝。當病毒感染時,TRIM14的賴氨酸Lys365位點發(fā)生K63多聚泛素化修飾,招募NEMO到MAVS信號小體,促使IRF3和NF-κB信號通路激活,正調控RIG-I介導的抗病毒免疫。I型干擾素能促進TRIM14的表達,從而增強先天免疫反應,對抗病毒感染[31]。E3泛素連接酶MIB2(mindbomb2)與MAVS上高度保守的DLAIS基序結合,促使TBK1的K63連接的泛素化修飾,并磷酸化激活IRF3/7,激活下游轉錄因子和誘導更多的IFN-β的生成[32];E3泛素連接酶RNF135,能促進RIG-I的C端結構域K63聚泛素化,從而增強病毒感染早期I型干擾素的生成[33]。E3泛素連接酶TRIM25能K63泛素化修飾RIG-I、MDA5與MAVS的復合物,并正調控抗病毒信號通路,RIG-I第172位賴氨酸是TRIM25介導的K63泛素化的關鍵位點,增強RIG-I與MAVS相互結合[34]。有趣的是,TRIM25還對全長MAVS的在第7和第10位賴氨酸位點發(fā)生K48泛素化介導的蛋白酶體降解,而這種降解正向調控抗病毒信號[14]。
除了對MAVS的泛素化修飾之外,磷酸化修飾也是MAVS正調控的主要方式。例如MAVS的酪氨酸Tyr9位點磷酸化激活下游IFN-β的信號傳導[35];酪氨酸激酶c-Abl直接與MAVS相互作用磷酸化MAVS,正調控MAVS介導的信號通路[36](圖1)。
圖1 MAVS介導的先天性免疫的調控Fig.1 The regulation of MAVS-mediated innate immunity
3.1 病毒蛋白裂解MAVS 許多病毒的蛋白具有蛋白酶功能,能夠通過切割MAVS來負調控MAVS介導的信號通路。例如丙肝病毒NS3-NS4A蛋白酶特異性識別位于MAVS的跨膜結構域半胱氨酸C508位點來切割MAVS,MAVS從線粒體膜上釋放,從而抑制下游I型干擾素和III型干擾素抗病毒信號通路[37]。與NS3/NS4A同源的犬肝炎病毒NS3、GB病毒B型NS3/4A,也能裂解MAVS,促使病毒免疫逃避[38,39]。除此以外,甲肝病毒的半胱氨酸蛋白酶的前體3C、乙肝病毒的HBX蛋白和腸道病毒71型的蛋白酶2A前體均可以裂解MAVS,從而阻斷下游信號轉導[40,41]??滤_奇病毒B3半胱氨酸蛋白酶前體3C介導MAVS,在富含脯氨酸的區(qū)域的谷氨酰胺Q148位點裂解,導致了MAVS在線粒體膜的重新定位并抑制下游信號通路[42]。豬繁殖與呼吸綜合征病毒的3C樣蛋白酶通過在蛋白酶體和獨立的含半胱氨酸的天冬氨酸蛋白水解酶(caspase)方式在谷氨酸Glu268位點切割MAVS,抑制病毒誘導IFN-β的產生[43]。
3.2 蛋白酶體降解MAVS 除了直接裂解MAVS之外,有些病毒能利用蛋白酶體降解MAVS途徑直接抑制MAVS。冠狀病毒編碼的開放閱讀框9B(ORF-9B)通過PCBP2介導的E3泛素連接酶AIP4降解MAVS、TRAF3和TRAF6的復合物。冠狀病毒SARS的ORF-9B能操縱宿主細胞的線粒體功能,以幫助其逃避宿主天然免疫[44]。輪狀病毒非結構蛋白1(NSP1)在感染后,介導MAVS通過蛋白酶體途徑被泛素化降解,抑制線粒體外膜上MAVS聚集體的形成,從而抑制了抗病毒信號級聯反應[45]。乙型肝炎病毒X蛋白對MAVS的賴氨酸Lys136位點進行泛素化修飾后,被蛋白酶體降解[46]。鯉春病毒血癥病毒(SVCV)的N蛋白可以通過經由泛素-蛋白酶體途徑降解斑馬魚的MAVS[47]。腸道病毒(CVB)感染細胞后,E3泛素連接酶Gp78通過蛋白酶體途徑和內質網關聯降解通路(ER-associated degradation)直接降解MAVS,Gp78也能與MAVS的N端、C端的結構域相結合,負調控MAVS介導的抗病毒信號轉導[48]。
3.3 與MAVS互作影響調控 病毒感染后,細胞內某些蛋白能夠與MAVS直接相互作用,阻礙下游接頭分子與MAVS結合。例如UBXN1(domaincontaining protein 1)能負調控RNA病毒誘導的I型干擾素反應。水泡口炎病毒、仙臺病毒、西尼羅河病毒、登革熱病毒等RNA病毒感染時,誘導生成的N端具有UBA結構域的泛素結合蛋白UBXN1特異性與MAVS結合,競爭TRAF3/6的結合位點(氨基酸第455-460位),阻礙MAVS招募TRAF3/6(TNF receptor-associated factor 3/6),干擾胞內的MAVS寡聚化,負調控MAVS下游信號通路[49]。
病毒蛋白與MAVS的互作也會通過影響線粒體上MAVS的集聚或改變MAVS的空間定位和構象,從而調控MAVS介導的通路。呼吸道合胞病毒(RSV)感染細胞后,非結構蛋白NS1與MAVS相結合,阻礙招募RIG-I的下游干擾素活化因子,如TRAF3、TRAF6和RIP1(receptor interacting protein-1)[50]。人類偏肺病毒(hMPV)的毒力因子M2-2蛋白通過與MAVS的互作抑制MAVS介導的細胞抗病毒反應,幫助偏肺病毒逃避先天性免疫[51]。甲型禽流感病毒(IAVAIV)H5N1的RNA聚合酶復合體PB2亞基通過直接相互作用于MAVS第1-37位氨基酸位點,阻礙MAVS的寡聚化和分子間構象變化,導致MAVS復合物的失活[52]。禽甲型流感病毒H5N1 RNA編碼的開放閱讀框(ORF)變化形成的毒力因子PB1-F2蛋白和PB2Δ蛋白都能用與MAVS在線粒體的相互作用,PB1-F2蛋白抑制宿主的先天免疫應答,PB2Δ蛋白增加甲型流感病毒誘導的I型干擾素表達,降低病毒復制水平[53,54]。Caspase募集域和膜相關鳥苷酸激酶樣結構域蛋白(CARD recruited membrane associated protein 3,CARMA3)作為宿主因子,在RNA病毒感染后,能抑制線粒體上MAVS的集聚,負調控RIG-I與MAVS介導的TBK1和IRF3激活[55]。
3.4 病毒感染后正調控 抗病毒反應與正調控MAVS介導的信號通路并不矛盾,病毒感染也可以正調控MAVS介導的信號通路。流感病毒感染時,鴨的TRIM27.1基因和TRIM27-L基因表達上調。TRIM家族蛋白是常見的E3泛素連接酶, TRIM27-L基因表達能強烈激活RIG介導的MAVS先天免疫信號,誘導抗病毒基因MX1和IFN-β的轉錄水平上調[56]。豬干擾素誘導蛋白三十四肽重復3(poIFIT3)是豬流感病毒(SIV)誘導出的基因之一,poIFIT3通過靶向MAVS ,誘導IFN-β水平上調,而且poIFIT3的過度表達可有效抑制SIV的復制[57]。腺病毒能共價結合補體C3進入細胞內,在細胞質內C3能增強激活線粒體抗病毒信號(MAVS)依賴的信號級聯和誘導促炎細胞因子的分泌[58](圖1)。
先天性抗病毒信號通路,作為第一道屏障消滅入侵的病原微生物,還避免了過度炎癥細胞損傷。作為先天性免疫的中樞蛋白,MAVS的精細調控,對于MAVS發(fā)揮功能和防止過度免疫反應至關重要。如上所述,細胞和病毒使用許多不同的機制來調控MAVS信號通路,包括轉錄和翻譯后修飾,與MAVS關聯的蛋白質-蛋白質相互作用。作為先天性免疫反應的中樞分子,越來越多的研究結果顯示:MAVS除了參與先天性免疫之外還參與了很多其他重要的細胞通路,例如細胞凋亡、細胞自噬等。反之其他通路的成分也被發(fā)現能夠通過調控MAVS來影響先天性免疫,例如自噬相關蛋白ATG5-ATG12等[7]。MAVS作為RLR信號通路中保守的接頭蛋白,在I型干擾素通路中起重要作用。動物病毒通過干擾MAVS,影響宿主干擾素反應,來逃避機體的抗病毒天然免疫。盡管近年來研究進展顯著,目前關于動物病毒抑制MAVS介導的干擾素表達機制的研究很少,尤其是禽類和水生動物類,大部分動物體內MAVS介導的抗病毒信號通路的調控機制不明確。通過對動物的MAVS介導的抗病毒天然免疫信號通路的調控機制還有待探索,有希望從該通路入手尋找到新的治療靶點來防治動物傳染病。
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THE REGULATION OF MAVS-MEDIATED ANTIVIRAL INNATE IMMUNITY
ZHENG Hang1, SUN Ying-jie2, ZHANG Pin3, DING Chan2
(1. College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China; 2. Shanghai Veterinary Research Institute, CAAS, Shanghai 200241, China; 3. College of Animal Science and Technology, Shandong Agricultural University, Taian 271018,China)
As the fi rst barrier of immune defense towards invading pathogens, the signaling pathway of the innate immunity plays an important role in antiviral response. The most important cytoplasmic pathogen recognition receptors are retinoic acid-inducible gene 1 and differentiation-associated protein 5. They possess the same downstream adaptor mitochondrial antiviral-signaling protein (MAVS).MAVS functions as the central molecular tool in innate immunity signaling pathway. MAVS-mediated signaling pathway is the important antiviral mechanism. However, viruses obtain a series of anti-MAVS mechanisms in the long-term coexistence status. Furthermore, cells in the resting state possess a number of MAVS regulation mechanisms to avoid excessive immune response. The delicate regulation of MAVS is critical for cell function and antiviral response. This review brie fl y introduces the structure and function as well as transcriptional and translational regulation mechanisms of MAVS. Furthermore, the mechanisms how viruses “fight back” MAVS-mediate innate immunity are elaborated. Understanding the regulation mechanism of MAVS may provide new insights into therapeutic strategies for the immunity regulation and virus infection.
Innate immunity; mitochondrial antiviral-signaling protein; pathogen; host
S852.42
A
1674-6422(2018)01-0081-08
2016-08-29
國家自然科學基金重點項目(31530074);國家自然科學基金面上項目(31372421);國家自然科學基金青年基金(31400144)
鄭航,男,碩士研究生,預防獸醫(yī)學專業(yè)
丁鏟,E-mail: shoveldeen @ shvri.ac.cn