當(dāng)細(xì)胞受到外界環(huán)境的刺激(如加熱、饑餓)時，細(xì)胞內(nèi)的蛋白質(zhì)和 RNA 分子會相互聚集，形成團(tuán)塊。長期以來，這些團(tuán)塊被認(rèn)為是細(xì)胞損傷的標(biāo)志，是有害的功能失調(diào)的分子，因而是需要被細(xì)胞清除掉的。例如，在阿爾茨海默氏病、帕金森氏病和肌萎縮性側(cè)索硬化(ALS)等神經(jīng)退行性疾病的患者大腦中，我們都能觀察到聚集成團(tuán)的蛋白質(zhì)累積在垂死的神經(jīng)元內(nèi)。近日，芝加哥大學(xué)的研究人員在《Cell》發(fā)文稱他們發(fā)現(xiàn)，水凝膠”態(tài)多肽蛋白質(zhì)能幫助細(xì)胞響應(yīng)刺激。在出芽酵母中存在一種名為 poly(A)結(jié)合蛋白(Pab1)的蛋白質(zhì)分子能夠通過形成團(tuán)塊來響應(yīng)外界刺激，幫助細(xì)胞渡過難關(guān)。

　　1.有益的蛋白質(zhì)聚集

　　這項(xiàng)研究中，研究人員試圖把 Pab1 團(tuán)塊分離出來。在顯微鏡下，那些團(tuán)塊看起來像圓形的水滴，與其說是團(tuán)塊，倒不如說是水凝膠，質(zhì)地有點(diǎn)像果凍或是牙膏。最重要的是，當(dāng)研究人員在活細(xì)胞中干擾這種水凝膠的形成時，這些細(xì)胞就失去了應(yīng)對外界刺激的能力。也就是說，Pab1 水凝膠的形成，非但沒有損害細(xì)胞的正常功能，還增強(qiáng)了細(xì)胞的適應(yīng)性。

　　“這種蛋白質(zhì)的聚集更像是一個有組織的緊急程序。就好像火災(zāi)警報時，人們離開原本的工作崗位，在特定的地方集合，以確保安全?！边@篇文章的通訊作者、芝加哥大學(xué)助理教授 Drummond 說，“對細(xì)胞而言，水凝膠的形成不僅能夠起到保護(hù)作用，還有調(diào)配的功能，比如打電話給消防隊(duì)員和護(hù)理人員?！?/p>

　　2.應(yīng)激機(jī)制?——相分離

　　近年來，大量的研究表明，形成蛋白質(zhì)液滴和水凝膠是細(xì)胞組織和重塑自身的重要方式。其中有一個過程——“相分離”——是水凝膠形成所必須的，就像沙拉醬中的油和醋，雖然都是液體，卻能夠彼此分開。為了發(fā)生相分離，之前的研究通常會使用極端的實(shí)驗(yàn)條件，如高濃度的蛋白質(zhì)或添加劑。而這項(xiàng)研究表明，細(xì)胞在受到外界刺激時，正常濃度的 Pab1 蛋白以及正常的細(xì)胞環(huán)境內(nèi)就可以發(fā)生相分離。

　　“令人驚訝的是，我們實(shí)際上并不知道這些細(xì)胞如何感受外界溫度的變化的，”Drummond 說，“動物具有感應(yīng)溫度變化的神經(jīng)元，但單細(xì)胞的酵母卻沒有。這種相分離過程的溫度敏感性遠(yuǎn)大于任何其他已經(jīng)描述的溫度傳感系統(tǒng)。因此，我們猜測這種通過形成水凝膠來感應(yīng)外界溫度和其他刺激的機(jī)制可能是廣泛存在的。”

　　Drummond 和他的同事們正在繼續(xù)研究這種相分離過程如何幫助細(xì)胞在刺激下生存的。在文章中，研究人員暗示這可能是因?yàn)?Pab1 在響應(yīng)刺激時能夠協(xié)助表達(dá)特定的 mRNA，這些 mRNA 翻譯出應(yīng)激蛋白，幫助細(xì)胞生長。

　　3.相分離的逆過程與疾病

　　除此之外，研究人員還在研究如何將 Pab1 的水凝膠液滴分散成單個分子。研究相分離的逆轉(zhuǎn)過程能夠幫助我們理解這一過程為什么會失敗。例如，在神經(jīng)退行性疾病(阿爾茨海默氏病、ALS 等)患者的神經(jīng)細(xì)胞中，蛋白質(zhì)團(tuán)塊的存在可能是細(xì)胞利用相分離過程應(yīng)對刺激的結(jié)果，是有益的。但問題是，細(xì)胞無法使這些團(tuán)塊返回到其正常狀態(tài)。

　　“我們找到了蛋白質(zhì)團(tuán)塊可能有利的第一個證據(jù)，” Drummond 說，“還有更多問題需要我們?nèi)ソ鉀Q，比如細(xì)胞是如何使用相分離過程來實(shí)現(xiàn)重要的功能，以及相分離這一可逆過程的故障如何導(dǎo)致疾病等?！?/p>

  When cells are stimulated by external environment (such as heating and starvation), the proteins and RNA molecules in the cell will aggregate together to form clumps. For a long time, these clumps are considered to be markers of cell damage and are malfunctioning and malfunctioning molecules, and therefore need to be removed by cells. For example, in the brain of patients with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS), we can all observe the accumulation of proteins in the dying neurons. Recently, researchers at the University of Chicago in the Cell said they found that a protein molecule called the poly (A) binding protein (Pab1) in the bud yeast can react to the external stimulus by forming a lump to help the cell survive the difficulty.

1. beneficial protein aggregation

In this study, researchers tried to separate the Pab1 masses. Under the microscope, the clusters look like round drops, rather than lumps, rather than hydrogels, which resemble jelly or toothpaste. Most importantly, when researchers interfere with the formation of such hydrogels in living cells, these cells lose the ability to respond to external stimuli. That is to say, the formation of Pab1 hydrogel not only does not damage the normal function of cells, but also enhances the adaptability of cells.

"The aggregation of this protein is more like an organized emergency procedure. Just like a fire alarm, people leave their jobs and assemble in specific places to ensure safety. "For cells, the formation of hydrogels can not only play a protective role, but also function, such as calling firefighters and nurses," said Drummond, an assistant professor at University of Chicago.

2. stress mechanism? - phase separation

In recent years, a large number of studies have shown that the formation of protein droplets and hydrogels is an important way of cell organization and remodeling itself. One of these processes, "phase separation", is necessary for the formation of hydrogels, like oil and vinegar in the salad dressing, which, though liquid, can be separated from each other. In order to occur phase separation, previous studies usually use extreme experimental conditions, such as high concentrations of protein or additives. This study shows that cells can undergo phase separation during normal stimulation of Pab1 protein and normal cell environment.

"Surprisingly, we don't really know how these cells feel the temperature changes in the outside world," Drummond said. "Animals have neurons that respond to temperature changes, but single cell yeasts do not. The temperature sensitivity of the phase separation process is much greater than that of any other temperature sensing system described. Therefore, we hypothesize that the mechanism by which hydrogel can induce external temperature and other stimuli may be widespread.

Drummond and his colleagues are continuing to study how this phase separation process helps cells survive under stimulation. In the article, the researchers suggest that this may be because Pab1 can help express specific mRNA in response to stimulus, which translates stress proteins to help cell growth.

The inverse process and disease of 3. phase separation

In addition, researchers are still studying how to disperse Pab1 hydrogel droplets into single molecules. Studying the reverse process of phase separation can help us understand why this process fails. For example, in the nerve cells of patients with neurodegenerative diseases (Alzheimer's disease, ALS, etc.), the presence of protein mass may be beneficial for the cell use phase separation process to respond to the results of stimulation. But the problem is that cells can't get these masses back to their normal state.

"We have found the first evidence that the protein mass may be beneficial," Drummond said. "There are more questions that need us to solve, such as how cells use the phase separation process to achieve important functions, and how the phase separation of the reversible process causes disease."