影響白念珠菌表型的信號通路及其轉(zhuǎn)錄因子研究進(jìn)展

王麗紅 張金宇 閻瀾 姜遠(yuǎn)英 曹永兵 洪浩

(1.中國藥科大學(xué)，南京 211198；2.第二軍醫(yī)大學(xué)藥學(xué)院新藥研究中心，上海 200433)

·綜述·

影響白念珠菌表型的信號通路及其轉(zhuǎn)錄因子研究進(jìn)展

王麗紅1,2張金宇2閻瀾2姜遠(yuǎn)英2曹永兵2洪浩1

(1.中國藥科大學(xué)，南京 211198；2.第二軍醫(yī)大學(xué)藥學(xué)院新藥研究中心，上海 200433)

白念珠菌是最常見的人類條件致病性真菌。白念珠菌在接受環(huán)境刺激信息后，能通過多種信號轉(zhuǎn)導(dǎo)途徑使菌體發(fā)生形態(tài)、毒力等各種表型轉(zhuǎn)換，從而適應(yīng)生長環(huán)境，易于在宿主體內(nèi)潛伏或致病。該文對白念珠菌表型轉(zhuǎn)換信號通路中主要轉(zhuǎn)錄因子的最新研究進(jìn)展進(jìn)行了概述，重點介紹介導(dǎo)白念珠菌形態(tài)轉(zhuǎn)換和毒力等表型的信號轉(zhuǎn)導(dǎo)主要通路：cAMP-PKA通路和MAPK通路，這些通路的終點都是相關(guān)轉(zhuǎn)錄因子，如Efg1、Cph1。轉(zhuǎn)錄因子能與基因啟動子結(jié)合，調(diào)控白念珠菌相應(yīng)基因的轉(zhuǎn)錄，從而促進(jìn)或抑制信號的傳達(dá)，影響白念珠菌的增殖、形態(tài)轉(zhuǎn)變、致病力等?？蔀橄嚓P(guān)研究工作者進(jìn)一步了解白念珠菌表型轉(zhuǎn)換的調(diào)節(jié)機制提供參考。

白念珠菌；表型；表型轉(zhuǎn)換；信號通路；轉(zhuǎn)錄因子

白念珠菌 (Candidaalbicans，C.albicans)，又稱為白假絲酵母菌，為條件性致病菌，在人體免疫力缺陷條件下易致病。人類感染性疾病死亡的首要原因是侵襲性念珠菌病，而白念珠菌感染是侵襲性念珠菌病的最主要病因，占所有病例的50%[1]。影響白念珠菌生長的環(huán)境因素主要有血清、氮源、碳源、氨基酸、溫度、pH等。白念珠菌通過調(diào)控自身形態(tài)轉(zhuǎn)換來適應(yīng)宿主體內(nèi)復(fù)雜的環(huán)境變化，酵母-菌絲轉(zhuǎn)換以及菌絲的生長與白念珠菌毒力和致病力密切相關(guān)，而黏附力及生物被膜形成能力在白念珠菌抵抗宿主免疫中十分重要[2]。白念珠菌細(xì)胞在接收各種外界環(huán)境信號后，通過各種信號轉(zhuǎn)導(dǎo)通路調(diào)控上述表型轉(zhuǎn)換。

目前已經(jīng)證實白念珠菌中幾種對不同環(huán)境信號應(yīng)答的表型轉(zhuǎn)換信號轉(zhuǎn)導(dǎo)通路，最常見兩條是環(huán)腺苷酸-蛋白激酶A (cAMP-protein kinase A，cAMP-PKA) 通路[3-5]和絲裂原活化蛋白激酶 (mitogen-activated protein kinase，MAPK)通路[6-7]。另外，有對pH敏感的RIM101 (regulator of IME2)通路和通過Ace2調(diào)節(jié)形態(tài)轉(zhuǎn)換的RAM (Regulation of Ace2 and Morphogenesis，RAM)通路等[8-9]。

轉(zhuǎn)錄因子 (Transcription factor，TF)能夠直接與基因的啟動子結(jié)合而調(diào)控該基因的轉(zhuǎn)錄，也可以和其他轉(zhuǎn)錄因子形成轉(zhuǎn)錄因子團(tuán)來影響基因的轉(zhuǎn)錄。TFs為基因調(diào)節(jié)網(wǎng)絡(luò)的中心，在白念珠菌的生命活動中扮演不可或缺的角色，對白念珠菌中的轉(zhuǎn)錄因子進(jìn)行更深一步的探討尤為重要[10]。本文主要綜述白念珠菌的酵母-菌絲轉(zhuǎn)換、黏附、生物被膜形成和毒力等表型相關(guān)調(diào)節(jié)通路中的轉(zhuǎn)錄因子及其生物學(xué)功能。

1 cAMP-PKA通路中的主要轉(zhuǎn)錄因子及其生物學(xué)功能

cAMP-PKA通路可調(diào)控白念珠菌對特異性環(huán)境刺激的應(yīng)答和調(diào)控各種特異性細(xì)胞表型的形成[11]。此通路的下游組分利用TF來調(diào)節(jié)每一種生長條件下特征性表型所需成分的基因表達(dá)。cAMP-PKA為各種因素誘導(dǎo)的形態(tài)轉(zhuǎn)換的最基本通路。在此通路中，胞外信號分子通過Ras1活化腺苷酸環(huán)化酶 (adenylyl cyclase，Cyr1)，Cyr1促進(jìn)cAMP生成，cAMP隨后激活PKA (包括兩個催化亞基Tpk1和Tpk2)，活性PKA磷酸化下游TFs而使TFs活化，從而調(diào)節(jié)基因表達(dá)[11-13]。

Efg1 (enhanced filamentous growth 1)被認(rèn)為是白念珠菌形態(tài)轉(zhuǎn)換中最主要TF。上位性分析顯示，Tpk2通過轉(zhuǎn)錄因子Efg1介導(dǎo)其下游信號[14]。Efg1屬于保守的APSES蛋白家族中含bHLH結(jié)構(gòu)的真菌特有的TF[15]。Efg1是能結(jié)合DNA上E-box (consensus sequence，5'-CANNTG-3')的序列特異性蛋白，E-box存在于大部分菌絲特異性基因的啟動子區(qū)域[16]。Efg1在蘇氨酸-206 (T206)有一個潛在Tpk2磷酸化位點，它的磷酸化直接影響白念珠菌形態(tài)轉(zhuǎn)換。T206位點突變生成不能磷酸化的非活性T206A，可阻止各種條件下的菌絲形成，而突變?yōu)榱姿峄鶊F(tuán)T206E會導(dǎo)致超級菌絲形成[17]。在致病力方面，efg1Δ/Δ是研究發(fā)現(xiàn)的第1種毒力減弱的白念珠菌。Efg1控制許多致病力相關(guān)的表型，包括在不同的細(xì)胞和載體上的黏附、37℃的菌絲形成、胃腸道定植和對抗菌藥的敏感性等[18-21]。有研究顯示，用白念珠菌系統(tǒng)性感染小鼠，48 h后檢測體內(nèi)白念珠菌的表達(dá)譜，與野生菌相比efg1Δ/Δ許多菌絲特異性基因表達(dá)下調(diào)，如ALS3、ECE1、HWP1、IHD1和SOD5[22]?？梢?，Efg1參與的cAMP-PKA信號通路不僅調(diào)節(jié)形態(tài)轉(zhuǎn)換，也調(diào)節(jié)毒力基因的表達(dá)。此外有研究顯示，efg1Δ/Δ在血清固體培養(yǎng)基和被巨噬細(xì)胞吞噬時也能形成菌絲[18]，且體內(nèi)的胃腸定植模型中許多體外依賴Efg1轉(zhuǎn)錄表達(dá)的基因也不再依賴于Efg1[23]。這表明PKA的下游還有其他轉(zhuǎn)錄因子。

白念珠菌中已經(jīng)證實在PKA下游起效的其他TFs中常見的一個是Flo8 (FLOcculation 8)，F(xiàn)lo8是含Lis-H結(jié)構(gòu)域的蛋白，flo8Δ/Δ在小鼠系統(tǒng)性感染模型中的毒力顯著下降[24]。

以上描述了Efg1和Flo8在白念珠菌中的單獨作用，但大多數(shù)情況下表型的發(fā)生或轉(zhuǎn)換需要轉(zhuǎn)錄因子對 (TF-TF)或轉(zhuǎn)錄因子團(tuán)才能調(diào)控完成。聯(lián)合ChIP-chip、模序結(jié)合位點、核小體占領(lǐng)和mRNA過表達(dá)等技術(shù)可以證明轉(zhuǎn)錄因子可結(jié)合成TF-TF而起效[24-25]。利用這些技術(shù)證明，在酵母和菌絲細(xì)胞中，F(xiàn)lo8和Efg1相互作用，F(xiàn)lo8調(diào)節(jié)一部分Efg1控制的基因，如菌絲生長調(diào)節(jié)基因HGC1[24]。另外，有研究證實Flo8的結(jié)合伴侶之一是Mss11，Mss11也是N端含LisH模序的轉(zhuǎn)錄因子[26]。MSS11過表達(dá)促進(jìn)菌絲生長，MSS11缺失會導(dǎo)致菌絲特異性基因表達(dá)和菌絲生長缺陷。細(xì)胞內(nèi)ChIP分析顯示Flo8和Mss11通過LisH模序相互作用，菌絲態(tài)細(xì)胞中基因HWP1啟動子上結(jié)合的Mss11和Flo8比酵母態(tài)細(xì)胞多，且應(yīng)答菌絲誘導(dǎo)時這兩個TFs的結(jié)合增加互相依賴。此外，過表達(dá)FLO8時可不通過Mss11促進(jìn)菌絲形成，但是過表達(dá)MSS11在flo8Δ/Δ不能促進(jìn)菌絲形成[27]。

白念珠菌中另一PKA下游常見轉(zhuǎn)錄因子是Tec1，Tec1屬于TEA/ATTS轉(zhuǎn)錄因子家族，tec1Δ/Δ菌絲形成缺陷，且在小鼠體內(nèi)毒力減弱[28]。另有研究顯示，tec1Δ/Δ黏附力、生物被膜合成、生物被膜厚度和β-葡聚糖釋放均低于野生菌[29]。tec1Δ/Δ中EFG1過表達(dá)不能影響形態(tài)轉(zhuǎn)換，而TEC1的過表達(dá)會恢復(fù)efg1Δ/Δ的部分表型，這表明Tec1可能在Efg1下游起效[28]。

白念珠菌不同的MTL (mating type-like)基因座類型會形成特征不同的生物被膜，白念珠菌的MTL基因座分為純合型 (MTLa/a和MTLα/α)和雜合型 (MTLa/α)[30-31]。MTLa/α菌株的生物被膜形成由cAMP-PKA通路調(diào)節(jié)，而MTLa/a和MTLα/α的生物被膜通過MAPK通路調(diào)節(jié)[29,31-32]。雜合型白念珠菌中轉(zhuǎn)錄因子形成一個緊密聯(lián)系的網(wǎng)絡(luò)來控制生物被膜形成，cAMP-PKA通路中Efg1、Tec1和Bcr1 (biofilm and cell wall regulator 1)研究最多。EFG1的功能缺失突變會導(dǎo)致生物被膜形成減少，而其過表達(dá)能彌補ras1、cyr1和tpk2缺失菌的被膜形成缺失，該實驗證明Efg1通過在上述基因的下游發(fā)揮功能調(diào)控白念珠菌的生物被膜形成[30]。鋅指轉(zhuǎn)錄因子Bcr1是生物被膜形成的中樞調(diào)節(jié)子之一，能激活體內(nèi)外生物被膜形成相關(guān)的菌絲黏附基因HWP1、ALS3和ECE1的表達(dá)[33]，bcr1Δ/Δ在硅膠導(dǎo)管材料中僅能形成不成熟的生物被膜[33-34]。

綜上，Efg1、Tec1和Bcr1均為雜合型生物被膜形成所需的轉(zhuǎn)錄因子。Efg1在Tec1的上游發(fā)揮功能，tec1Δ/Δ中BCR1過表達(dá)可使生物被膜生長恢復(fù)，而bcr1Δ/Δ過表達(dá)TEC1不能恢復(fù)生物被膜生長，這表明Tec1直接調(diào)節(jié)Bcr1，Bcr1可能在Tec1的下游起效[35]。

2MAPK通路中的主要轉(zhuǎn)錄因子及其生物學(xué)功能

MAPK通路包含三個激酶：MAPK，MAPKK (包括Hst7、Pbs2和Mkk1等)，MAPKKK (包括Ste11、Ssk2和Bck1等)。在一些刺激下MAPKKK、MAPKK和 MAPK依次被磷酸化激活，活性MAPK通過調(diào)節(jié)下游TF，使白念珠菌產(chǎn)生一個特定的自適應(yīng)反應(yīng)[36]。白念珠菌中MAPK通路與真核生物細(xì)胞分化和增殖的調(diào)控有關(guān)[37]，根據(jù)白念珠菌中MAPK的種類，此通路分為四類：①菌絲態(tài)形成(Cek1)通路；②交配(Cek2)通路；③高滲甘油應(yīng)答(high osmolarity glycerol response，HOG )通路；④細(xì)胞壁完整性(the cell wall integrity，Mkc1)通路[36,38]。

Cek1活化MAPK通路的轉(zhuǎn)錄因子Cph1，Cph1的識別模序是TGAAACA[39]。通過系統(tǒng)敲除法，Maiti等[40]證明了 Cph1的N端同源結(jié)構(gòu)為結(jié)合DNA功能區(qū)域，而C端結(jié)構(gòu)和多聚尾模序(PQ)是轉(zhuǎn)錄活性功能區(qū)域。Cph1結(jié)合位點分析、基因組分析以及RT-PCR轉(zhuǎn)錄分析揭示，Cph1的轉(zhuǎn)錄靶標(biāo)為與菌絲生長、維持細(xì)胞壁結(jié)構(gòu)以及線粒體功能有關(guān)的基因和pH應(yīng)答通路的基因[40-42]。

cph1Δ/Δ在Spider固體培養(yǎng)基中僅能延遲菌絲生長，在血清培養(yǎng)基中菌絲生長與野生菌無差異[43]，且也能引起小鼠致命性感染[18]，在cph1Δ/Δ中僅部分菌絲特異性基因表達(dá)下降[17]，可知Cph1不是白念珠菌菌絲生長的關(guān)鍵轉(zhuǎn)錄因子。但Cph1能調(diào)控幾丁質(zhì)合成相關(guān)基因 (CHS1，CHS8和UAP1)、外層細(xì)胞壁GPI錨定蛋白相關(guān)基因 (HWP1和ECE1)和線粒體相關(guān)基因 (ATP17、MDM12和TIM9)的表達(dá)，表明Cph1在細(xì)胞壁構(gòu)成和氧化應(yīng)激過程中發(fā)揮重要作用[40]。

GABA型的鋅指轉(zhuǎn)錄因子Gat2在白念珠菌被膜形成、菌絲形成和毒力中扮演重要角色[44]。gat2Δ/Δ不能在聚乙烯類和聚硅酮類材料的表面形成生物被膜，且過表達(dá)GAT2能在固體Lee’s培養(yǎng)基上促進(jìn)菌絲生長。小鼠系統(tǒng)性感染模型中，gat2Δ/Δ毒力顯著減弱[45]。序列分析結(jié)果表明，Tec1在基因GAT2上有兩個啟動子結(jié)合序列(TCATTCT和ACATTCT)[46]。此外，GlcNAc誘導(dǎo)菌絲生長不需要Tec1和Gat2，但是SD-葡萄糖培養(yǎng)基誘導(dǎo)菌絲生長需要Tec1和Gat2。由此可見，Gat2可能在Tec1的下游起調(diào)節(jié)菌的形態(tài)轉(zhuǎn)變和生物被膜生長的作用[45]。

綜上可知，Tec1在cAMP-PKA通路和MAPK通路均扮演重要角色，從而將cAMP-PKA通路和MAPK通路緊密聯(lián)系起來。

MAPK通路中與耐藥相關(guān)的轉(zhuǎn)錄因子有鋅指轉(zhuǎn)錄因子Cas5?；蚪M轉(zhuǎn)錄分析證實Cas5能促進(jìn)白念珠菌中細(xì)胞壁相關(guān)基因 (如PGA13和PGA31)和與離子轉(zhuǎn)運、結(jié)合和動態(tài)平衡相關(guān)的基因(包括CFL2、CFL4、FET34和FRE1)的表達(dá)，這些基因均與氟康唑耐藥相關(guān)[47]。另有研究顯示，cas5Δ/Δ中卡泊芬凈誘導(dǎo)表達(dá)的基因CRH11和ECM331的表達(dá)也下調(diào)，諾瑟雜交分析進(jìn)一步證實基因CRH11和ECM331的表達(dá)缺失。不過CRH11和ECM331不是應(yīng)答卡泊芬凈的最關(guān)鍵基因，所以Cas5可能是調(diào)控應(yīng)答細(xì)胞壁損傷基因的轉(zhuǎn)錄因子之一[48]。因此，對Cas5的進(jìn)一步研究可能有助于找到增強唑類和棘白素類抗菌藥活性的靶點。

3 其他通路及相關(guān)轉(zhuǎn)錄因子

Rim101為鋅指轉(zhuǎn)錄因子，環(huán)境pH通過RIM101通路影響白念珠菌形態(tài)。環(huán)境pH水平可影響白念珠菌細(xì)胞壁蛋白Rim21，Rim21隨后傳遞分子信號到Rim8、Rim13、Rim20，而后活化轉(zhuǎn)錄因子Rim101和Efg1，進(jìn)而調(diào)節(jié)菌絲特異性基因，如HGC1、ECE1、HWP1和ALS家族[49]。另外，Ace2為白念珠菌特有的轉(zhuǎn)錄因子，通過RAM通路直接發(fā)揮調(diào)控細(xì)胞分離、黏附、動物體內(nèi)毒力和生物被膜形成等作用[50-51]。RAM通路和cAPM-PKA通路共同調(diào)節(jié)菌絲生長，Efg1和Ace2在細(xì)胞內(nèi)周期性調(diào)節(jié)形態(tài)轉(zhuǎn)換過程，這兩條通路在不同階段活化。在酵母和菌絲態(tài)細(xì)胞中Ace2都位于子細(xì)胞細(xì)胞核[52]，而Efg1在菌絲誘導(dǎo)后迅速下調(diào)[53]。因而，一般認(rèn)為Efg1在形態(tài)發(fā)生早期對共調(diào)節(jié)基因的表達(dá)更重要，而Ace2在菌絲出現(xiàn)子細(xì)胞核時的形態(tài)發(fā)生后期起主要作用。

4 討 論

白念珠菌中編碼TFs的基因缺失會導(dǎo)致毒力顯著下降，TFs整合來源于環(huán)境的信號，并通過調(diào)節(jié)基因轉(zhuǎn)錄而介導(dǎo)適應(yīng)性應(yīng)答，阻礙與特異性宿主條件下應(yīng)答相關(guān)的TF可能會使白念珠菌生存的適應(yīng)性應(yīng)答缺陷。因此，轉(zhuǎn)錄調(diào)節(jié)模式對白念珠菌在多變的宿主微環(huán)境生存中有重要的作用。它們可能已經(jīng)形成了一種集中調(diào)節(jié)系統(tǒng)以確?；蛟谇忠u不同階段表達(dá)到合適的水平，這些基因的產(chǎn)物能使白念珠菌侵襲和破壞特定微環(huán)境的宿主細(xì)胞。白念珠菌的致病性主要包括黏附宿主細(xì)胞和生物被膜形成，而文中TFs或TFs調(diào)控的基因在白念珠菌的致病性中發(fā)揮關(guān)鍵作用，因此這些TFs或TFs調(diào)控的基因可作為潛在的抗白念珠菌感染治療新型藥物靶標(biāo)。雖然目前對白念珠菌表型變化所需的信號和影響因素的認(rèn)識已經(jīng)取得巨大進(jìn)步，但是對基因調(diào)控這些過程的認(rèn)識仍然不全面。白念珠菌仍有許多轉(zhuǎn)錄因子未被揭曉，其轉(zhuǎn)錄活化或抑制的上游調(diào)節(jié)子仍未被發(fā)現(xiàn)，且目前仍未找到能抑制或上調(diào)TF的物質(zhì)。白念珠菌是一個完整的生命有機體，其信號轉(zhuǎn)導(dǎo)通路十分復(fù)雜，本文的闡述只是其中一部分，要掌握白念珠菌控制和協(xié)助形態(tài)轉(zhuǎn)換和毒力等基因表達(dá)復(fù)雜調(diào)控網(wǎng)絡(luò)的概圖，需要更深入的研究和探索。

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[本文編輯] 王 飛

The transcription factors of phenotypic transition signal pathways inCandidaalbicans

WANG Li-hong1,2,ZHANG Jin-yu2,YAN Lan2,JIANG Yuan-ying2,CAO Yong-bing2,HONG Hao1

(1.ChinaPharmaceuticalUniversity,Nanjing211198,China;2.NewDrugResearchCenterofSecondMilitaryMedicalUniversity,Shanghai200433,China)

Candidaalbicans,responsing signals to adapt to environment by a variety of signal transduction pathways,is the most common human opportunistic fungi.The most important signal transduction pathways that mediate the morphogenesis and virulence inCandidaalbicansare cAMP-PKA pathway and MAPK pathway.Transcription factors are the endpoints of these pathways,such as Efg1 and Cph1.Transcription factors can regulate the transcription of genes by binding with their promoters inCandidaalbicans.Regulating transcription factors can promote or inhibit the signal transduction,and thus affecting the proliferation,morphogenesis,virulence,etc,ofCandidaalbicans.In this review,we demonstrated the major transcription factors of phenotypic transition signal pathways inCandidaalbicansto further understand the phenotype and regulation mechanism ofCandidaalbicans.

C.albicans;phenotype;phenotypic transition;signal pathways;TF

114-119]

國家自然科學(xué)基金 (81273556，81673478)

王麗紅，女 (漢族)，碩士研究生在讀.E-mail:995822188@qq.com

洪浩,E-mail:honghao@cpu.edu.cn;曹永兵,E-mail:ybcao@vip.sina.com

R 379.4

A

1673-3827(2017)12-0114-06

2016-11-03