近日,，國際著名雜志PNAS在線刊登了中科院上海生物化學(xué)與細(xì)胞生物學(xué)研究所所長林安寧研究組的最新研究成果“Site-specific ubiquitination is required for relieving the transcription factor Miz1-mediated suppression on TNF-α–induced JNK activation and inflammation,，”，文章中,，作者解釋了一種TNF-α–induced JNK信號(hào)調(diào)節(jié)的新機(jī)制,。
細(xì)胞信號(hào)轉(zhuǎn)導(dǎo)在諸如增殖、分化,、程序性死亡,、轉(zhuǎn)化等細(xì)胞活動(dòng)的調(diào)控中都扮演了至關(guān)重要的角色，但信號(hào)轉(zhuǎn)導(dǎo)調(diào)控異常的發(fā)生往往會(huì)導(dǎo)致很多人類疾病甚至癌癥,。細(xì)胞外的各種信號(hào)通過一個(gè)由眾多信號(hào)轉(zhuǎn)導(dǎo)通路構(gòu)成的細(xì)胞內(nèi)信號(hào)轉(zhuǎn)導(dǎo)網(wǎng)絡(luò)（intracellular signaling network）傳輸?shù)郊?xì)胞內(nèi)部,，從而調(diào)控至關(guān)重要的細(xì)胞活動(dòng)。雖然細(xì)胞內(nèi)信號(hào)轉(zhuǎn)導(dǎo)網(wǎng)絡(luò)結(jié)構(gòu)已經(jīng)相當(dāng)清楚,，但信號(hào)網(wǎng)絡(luò)在人體內(nèi)的生物學(xué)作用與調(diào)控尚有待進(jìn)一步研究,。
林安寧研究組主要從事癌癥信號(hào)轉(zhuǎn)導(dǎo)網(wǎng)絡(luò)與基因調(diào)控的分子機(jī)理方面的研究，實(shí)驗(yàn)室的工作主要是利用c-Jun N-terminal protein kinase (JNK)和IkB kinase(IKK)/NF-kappaB等分子探針來研究決定信號(hào)轉(zhuǎn)導(dǎo)網(wǎng)絡(luò)的可塑性和特異性的分子機(jī)制,，試圖理解信號(hào)轉(zhuǎn)導(dǎo)網(wǎng)絡(luò)調(diào)控的異常怎樣導(dǎo)致人類疾病和癌癥,。
TNF-α是一個(gè)多向性的先導(dǎo)感染細(xì)胞因子，包括NF-κB,、JNK,、caspases，可以通過激活下游的信號(hào)路徑調(diào)節(jié)很多免疫反應(yīng),、細(xì)胞死亡,、炎癥以及腫瘤的產(chǎn)生，目前,，對于JNK途徑有選擇性地調(diào)節(jié)是否是通過影響其他信號(hào)通路如TNF-α等并不是很清楚,，最近有報(bào)道稱Miz1可以充當(dāng)信號(hào)途徑SMORs來有選擇性的調(diào)節(jié)TNF-α誘導(dǎo)的JNK的激活和細(xì)胞的凋亡，但是具體的機(jī)制并不清楚,；作者在他們的研究中報(bào)道,，Miz1通過干擾泛素偶聯(lián)酶Ubc13和TRAF2（TNF受體因子）的結(jié)合來抑制TRAF2 E3連接酶的活性，進(jìn)而抑制了TRAF2 K63連鎖的聚泛素和JNK1的激活,；在TNF-α的刺激下,，Miz1可以在388位和472位賴氨酸的殘基上進(jìn)行聚泛素化，隨后以TRAF2依賴的方式進(jìn)行降解,，通過精氨酸可以替代這兩個(gè)賴氨酸位點(diǎn),，進(jìn)而產(chǎn)生一個(gè)非降解的Miz1的突變體，這個(gè)突變體可以明顯抑制由TNF-α誘導(dǎo)的JNK1的激活和炎癥的發(fā)生,。
作者的研究揭示了一種新的分子機(jī)制,，即通過Miz1抑制TNF-α-JNK的激活可以通過自身特殊位點(diǎn)的遍在蛋白化和降解來進(jìn)行脫阻抑。（生物谷Bioon.com）
（T.Shen編譯 如有問題請及時(shí)指正）
doi:10.1073/pnas.1105176108
PMC:
PMID:
Site-specific ubiquitination is required for relieving the transcription factor Miz1-mediated suppression on TNF-α–induced JNK activation and inflammation
Jing Liua,1, Jie Yana, Shan Jiangb, Jing Wenb, Long Chenb, Yingming Zhaoa, and Anning Lina,b,2
The transcription factor zinc-finger protein Miz1 represses TNF-α–induced JNK activation and the repression is relieved upon TNF-α stimulation. However, the underlying mechanism is incompletely understood. Here we report that Miz1 interferes with the ubiquitin conjugating enzyme (E2) Ubc13 for binding to the RING domain of TNF-receptor associated factor 2 (TRAF2), thereby inhibiting the ubiquitin ligase (E3) activity of TRAF2 and suppressing TNF-α–induced JNK activation. Upon TNF-α stimulation, Miz1 rapidly undergoes K48-linked polyubiquitination at Lys388 and Lys472 residues and subsequent proteasomal degradation in a TRAF2-dependent manner. Replacement of Lysine 388 and Lysine 472 by arginines generates a nondegradable Miz1 mutant, which significantly suppresses TNF-α–induced JNK1 activation and inflammation. Thus, our results reveal a molecular mechanism by which the repression of TNF-α–induced JNK activation by Miz1 is de-repressed by its own site-specific ubiquitination and degradation, which may account for the temporal control of TNF-α–JNK signaling.
