生物谷报道：线粒体是细胞的“能量中心”，为细胞的正常活动提供能量。现在，研究人员在线粒体中发现了一种出乎意料的“潜水员”。他们发现线粒体含有一种能够引发免疫系统攻击病毒入侵者的蛋白质。这种新的功能蛋白的发现具有非常重要的生物学和进化意义，因为它与线粒体作为引发细胞凋亡的生化级联的执行者的功能相呼应。
这个蛋白是目前为止人们知道的第一个在线粒体中发现的与免疫应答有关的蛋白。霍华德休斯医学院的Zhijian ‘James’ Chen和同事将研究的结果公布在8月26日的Cell杂志上。
研究中，Chen和同事寻找一种能够连接两种重要的先天免疫系统触发因子NF-kB和IRF3活化作用的调节性分子。不知何故，这些分子被一种叫做RIG-1的受体分子活化，而这种受体能够检测病毒的遗传物质。RIG-I能与病毒（如流感病毒、丙肝病毒、西尼罗河病毒和SARS病毒）的RNA结合。
研究人员已经知道他们寻找的这种分子就存在于RIG-1和其他“下游”调节分子之间的一个生化途径中的某个位置。为了寻找这个丢失的分子，他们首先搜索了细胞中含有一种特殊的分子区域——CARD区域（CARD domain）的蛋白质。CARD区域介导不同调节蛋白之间的相互作用。他们的研究发现了线粒体抗病毒信号途径中的一种蛋白，并将之命名为MAVS。
实验表明MAVS活化了培养的细胞中的NF-kB和IRF3。他们还发现MAVS要想正常行使功能则同时需要CARD结构域和另外一个将它停泊到线粒体膜上的结构域。研究使用荧光示踪物揭示出MAVS存在于细胞的线粒体中。而且，当研究人员改变MAVS分子使它无法与线粒体结合时，这种分子就不能正常行使功能。
他们发现没有MAVS的细胞容易受到病毒的感染，而含有过量MAVS的细胞对这些感染产生抗性——这意味着MAVS在免疫应答中起到重要的作用。
Chen推测线粒体可能因为靠近细胞内膜（病毒复制发生的位置）而进化成为免疫“哨兵”。了解促进MAVS功能如何导致细胞对病毒感染产生抗性的原理具有重要的临床意义，并且能够提高MAVS活性的治疗方法可能有效促进对病毒的免疫反应。
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.”
