生物谷報(bào)道：線粒體是細(xì)胞的“能量中心”，為細(xì)胞的正?；顒?dòng)提供能量?，F(xiàn)在，研究人員在線粒體中發(fā)現(xiàn)了一種出乎意料的“潛水員”,。他們發(fā)現(xiàn)線粒體含有一種能夠引發(fā)免疫系統(tǒng)攻擊病毒入侵者的蛋白質(zhì),。這種新的功能蛋白的發(fā)現(xiàn)具有非常重要的生物學(xué)和進(jìn)化意義，因?yàn)樗c線粒體作為引發(fā)細(xì)胞凋亡的生化級(jí)聯(lián)的執(zhí)行者的功能相呼應(yīng),。
這個(gè)蛋白是目前為止人們知道的第一個(gè)在線粒體中發(fā)現(xiàn)的與免疫應(yīng)答有關(guān)的蛋白,。霍華德休斯醫(yī)學(xué)院的Zhijian ‘James’ Chen和同事將研究的結(jié)果公布在8月26日的Cell雜志上,。
研究中,，Chen和同事尋找一種能夠連接兩種重要的先天免疫系統(tǒng)觸發(fā)因子NF-kB和IRF3活化作用的調(diào)節(jié)性分子。不知何故,，這些分子被一種叫做RIG-1的受體分子活化,，而這種受體能夠檢測(cè)病毒的遺傳物質(zhì)。RIG-I能與病毒（如流感病毒,、丙肝病毒,、西尼羅河病毒和SARS病毒）的RNA結(jié)合。
研究人員已經(jīng)知道他們尋找的這種分子就存在于RIG-1和其他“下游”調(diào)節(jié)分子之間的一個(gè)生化途徑中的某個(gè)位置,。為了尋找這個(gè)丟失的分子,，他們首先搜索了細(xì)胞中含有一種特殊的分子區(qū)域——CARD區(qū)域（CARD domain）的蛋白質(zhì)。CARD區(qū)域介導(dǎo)不同調(diào)節(jié)蛋白之間的相互作用,。他們的研究發(fā)現(xiàn)了線粒體抗病毒信號(hào)途徑中的一種蛋白,，并將之命名為MAVS。
實(shí)驗(yàn)表明MAVS活化了培養(yǎng)的細(xì)胞中的NF-kB和IRF3,。他們還發(fā)現(xiàn)MAVS要想正常行使功能則同時(shí)需要CARD結(jié)構(gòu)域和另外一個(gè)將它停泊到線粒體膜上的結(jié)構(gòu)域,。研究使用熒光示蹤物揭示出MAVS存在于細(xì)胞的線粒體中。而且,，當(dāng)研究人員改變MAVS分子使它無(wú)法與線粒體結(jié)合時(shí),，這種分子就不能正常行使功能,。
他們發(fā)現(xiàn)沒(méi)有MAVS的細(xì)胞容易受到病毒的感染，而含有過(guò)量MAVS的細(xì)胞對(duì)這些感染產(chǎn)生抗性——這意味著MAVS在免疫應(yīng)答中起到重要的作用,。
Chen推測(cè)線粒體可能因?yàn)榭拷?xì)胞內(nèi)膜（病毒復(fù)制發(fā)生的位置）而進(jìn)化成為免疫“哨兵”,。了解促進(jìn)MAVS功能如何導(dǎo)致細(xì)胞對(duì)病毒感染產(chǎn)生抗性的原理具有重要的臨床意義，并且能夠提高M(jìn)AVS活性的治療方法可能有效促進(jìn)對(duì)病毒的免疫反應(yīng),。
原文：
Researchers have discovered a surprise lurking inside mitochondria, the power plants that are present in every cell. It turns out that these powerhouses also contain a protein that triggers the immune system to attack viral invaders.
According to the researchers, the new role makes perfect biological and evolutionary sense because it fits well with another function of mitochondria as executioners of a biochemical cascade that causes programmed cell death, or apoptosis.
“This is the first protein known to be involved in the immune response that is found in mitochondria,” said Zhijian `James’ Chen, a Howard Hughes Medical Institute investigator at the University of Texas Southwestern Medical Center. Chen and his colleagues reported the discovery on August 25, 2005, in an immediate early publication of the journal Cell.
In their studies, Chen and his colleagues were seeking a regulatory molecule that would provide a missing link in the activation of two important triggers of the innate immune system — NF-kB and IRF3. Somehow, these molecules are activated in response to a receptor molecule, called RIG-I, which detects viral genetic material. RIG-I binds to the RNA of viruses such as the influenza virus, hepatitis C virus, West Nile virus and SARS virus.
The researchers knew the molecule they were seeking was present in a biochemical pathway somewhere between RIG-I and other “downstream” regulatory molecules. They initiated a search for this missing molecule by searching for proteins in the cell that contain a characteristic molecular domain, called a CARD domain, which mediates interactions between different regulatory proteins. Their search yielded a protein, which they called MAVS for mitochondrial antiviral signaling.
Their experiments revealed that MAVS activated NF-kB and IRF3 in cell cultures. They also found that in order for MAVS to function, it requires both the CARD domain and another domain that anchors it to the mitochondrial membrane. Studies using fluorescent tracers revealed that MAVS was present in the mitochondria of cells. And when the researchers altered the MAVS molecule in such a way that it prevented MAVS from attaching to mitochondria, the molecule did not function properly.
The researchers demonstrated the importance of MAVS in immune responses by showing that cells without MAVS were vulnerable to viral infection; while those with excess MAVS were resistant to such infections.
Chen speculated that the mitochondria might have evolved into immune sentinels because of their location near internal cell membranes where viral replication takes place. “By having MAVS in the mitochondrial membrane, it provides a strategic position for cells to sense the presence of viruses, especially viral replication,” said Chen.
“In addition, MAVS is unique in that it has both a mitochondrial targeting sequence, as well as a CARD domain sequence,” said Chen. “CARD domain proteins are known to be involved in apoptosis, and the mitochondria are also known to be involved in apoptosis. So, while at this point this is still pure speculation, but perhaps combining these two domains in one protein, MAVS, might allow the cells to integrate signals somehow and coordinate apoptotic responses or immune responses, depending on the type of viral infection.” Apoptosis is triggered when a cell is no longer needed during development or is damaged beyond repair. It serves to protect the body from the accumulation of damaged or malfunctioning cells.
Chen said that the newly discovered immunological service rendered to the cell by mitochondria makes good biological and evolutionary sense. “Evolutionarily, it is believed that mitochondria originated from ancient bacteria, which formed a symbiotic relationship with eukaryotic cells,” said Chen. “For symbiosis to evolve, the bacteria and the host must be beneficial to one another. Mitochondria have long been known to serve the major function of producing chemical energy for the cell, as well as to sense damage and trigger apoptosis. Now, I think our discovery reveals another important function of the mitochondria, and that is in immunity,” he said.
Understanding how boosting MAVS function causes cells to resist viral infection could have important clinical implications, said Chen. “Treatments that enhance the activity of MAVS may prove to be useful in boosting immunity against viruses,” he said. “Furthermore, we suspect that MAVS might be a prime target for some viruses that can evade immune surveillance. If those suspicions prove out, then treatments that counteract this evasion could provide therapeutic benefits,” he said. Chen also speculated that subtle variations in the MAVS protein might explain why people may respond differently when infected with the same virus.
Chen and his colleagues are now exploring such questions, as well as teasing out further molecular details of the signaling mechanism by which MAVS triggers the immune system. “Over the long term, we would like to understand the host-viral interactions that function through MAVS, and how MAVS gives the cell immunity to viruses and how viruses try to evade this function of MAVS. We would like to exploit these findings to develop more effective antiviral strategies.”
