Cellular Power Plants Also Fend Off Viruses

According to theresearchers, the new role makes perfect biological and evolutionarysense because it fits well with another function of mitochondria asexecutioners of a biochemical cascade that causes programmed celldeath, or apoptosis.

“This is the first protein known to beinvolved in the immune response that is found in mitochondria,” saidZhijian `James' Chen, a Howard Hughes Medical Institute investigator atthe University of Texas Southwestern Medical Center. Chen and hiscolleagues reported the discovery on August 25, 2005, in an immediateearly publication of the journal Cell.

In their studies, Chen andhis colleagues were seeking a regulatory molecule that would provide amissing link in the activation of two important triggers of the innateimmune system — NF-kB and IRF3. Somehow, these molecules are activatedin response to a receptor molecule, called RIG-I, which detects viralgenetic material. RIG-I binds to the RNA of viruses such as theinfluenza virus, hepatitis C virus, West Nile virus and SARS virus.

Theresearchers knew the molecule they were seeking was present in abiochemical pathway somewhere between RIG-I and other “downstream”regulatory molecules. They initiated a search for this missing moleculeby searching for proteins in the cell that contain a characteristicmolecular domain, called a CARD domain, which mediates interactionsbetween different regulatory proteins. Their search yielded a protein,which they called MAVS for mitochondrial antiviral signaling.

Theirexperiments revealed that MAVS activated NF-kB and IRF3 in cellcultures. They also found that in order for MAVS to function, itrequires both the CARD domain and another domain that anchors it to themitochondrial membrane. Studies using fluorescent tracers revealed thatMAVS was present in the mitochondria of cells. And when the researchersaltered the MAVS molecule in such a way that it prevented MAVS fromattaching to mitochondria, the molecule did not function properly.

Theresearchers demonstrated the importance of MAVS in immune responses byshowing that cells without MAVS were vulnerable to viral infection;while those with excess MAVS were resistant to such infections.

Chenspeculated that the mitochondria might have evolved into immunesentinels because of their location near internal cell membranes whereviral replication takes place. “By having MAVS in the mitochondrialmembrane, it provides a strategic position for cells to sense thepresence of viruses, especially viral replication,” said Chen.

“Inaddition, MAVS is unique in that it has both a mitochondrial targetingsequence, as well as a CARD domain sequence,” said Chen. “CARD domainproteins are known to be involved in apoptosis, and the mitochondriaare also known to be involved in apoptosis. So, while at this pointthis is still pure speculation, but perhaps combining these two domainsin one protein, MAVS, might allow the cells to integrate signalssomehow and coordinate apoptotic responses or immune responses,depending on the type of viral infection.” Apoptosis is triggered whena cell is no longer needed during development or is damaged beyondrepair. It serves to protect the body from the accumulation of damagedor malfunctioning cells.

Chen said that the newly discoveredimmunological service rendered to the cell by mitochondria makes goodbiological and evolutionary sense. “Evolutionarily, it is believed thatmitochondria originated from ancient bacteria, which formed a symbioticrelationship with eukaryotic cells,” said Chen. “For symbiosis toevolve, the bacteria and the host must be beneficial to one another.Mitochondria have long been known to serve the major function ofproducing chemical energy for the cell, as well as to sense damage andtrigger apoptosis. Now, I think our discovery reveals another importantfunction of the mitochondria, and that is in immunity,” he said.

Understandinghow boosting MAVS function causes cells to resist viral infection couldhave important clinical implications, said Chen. “Treatments thatenhance the activity of MAVS may prove to be useful in boostingimmunity against viruses,” he said. “Furthermore, we suspect that MAVSmight be a prime target for some viruses that can evade immunesurveillance. If those suspicions prove out, then treatments thatcounteract this evasion could provide therapeutic benefits,” he said.Chen also speculated that subtle variations in the MAVS protein mightexplain why people may respond differently when infected with the samevirus.

Chen and his colleagues are now exploring such questions,as well as teasing out further molecular details of the signalingmechanism by which MAVS triggers the immune system. “Over the longterm, we would like to understand the host-viral interactions thatfunction through MAVS, and how MAVS gives the cell immunity to virusesand how viruses try to evade this function of MAVS. We would like toexploit these findings to develop more effective antiviral strategies.”