Friday, March 10, 2006
'Jumping Genes': New Target For Body's Innate Immune Protection System Against Viruses
When HIV and other retroviruses invade a cell in the human body, a fierce battle ensues between the intruder and the cell's defense team: members of the APOBEC family, a handful of closely related antiviral proteins that try to disarm the invading virus by scrambling its genetic information.
But not every family member pitches in. One family member, APOBEC3A or A3A, is conspicuously absent when other APOBECs are battling HIV. Now, scientists at the Salk Institute for Biological Studies have discovered that A3A, the falsely accused deserter, specializes in defending against two different kinds of invaders: "jumping genes," pieces of DNA that can leap from one place in the human genome to another, and Adeno-associated virus (AAV), a tiny harmless virus very different from HIV.
The scientists report their findings in the current online edition of Current Biology .
"People thought that this particular family member didn't warrant a lot of attention because it didn't seem to do anything. But it turned out to have a very powerful effect when we looked in the right place," said Nathaniel Landau, Ph.D., professor in the Infectious Disease Laboratory at the Salk.
And the lab of his colleague Matthew Weitzman, Ph.D., at the Salk's Laboratory of Genetics turned out to be the perfect place.
"Together, we could not only assign a new function to a APOBEC family member that previously had none, but we also expanded the repertoire of different types of viruses against which this innate antiviral system is effective," said associate professor Weitzman, Ph.D., who studies virus-host interactions using Adeno-associated virus or AAV. "This implies that different members of the APOBEC family may have evolved to defend the cell against different types of parasites," he added.
To disarm the virus, members of the APOBEC family edit the genetic information carried by the virus, mutating it so badly that the virus can't function any longer. To do this, the APOBEC proteins remove an essential chemical group from cytosine, one of the four building blocks of DNA that spell out the genetic code, turning the DNA's message into gibberish.
Throughout evolution, cells had to defend themselves against the attack of viruses and "jumping genes," also called mobile genetic elements and either side could win these battles. Nowadays, mobile elements are mostly inactive, but since they successfully invaded the human genome millions of years ago, they are part of each person's genetic code, and their remnants account for more than 45 percent of our DNA. "In the case of HIV, the virus won the battle and it will spread through the human population until human ingenuity can outwit it," said Landau.
One group of "jumping genes" called retrotransposons is closely related to HIV but unlike their feared cousin have lost the ability to escape from their host cell. Marooned inside, they can only move via a "copy and paste" mechanism, taking up ever more space in their host's genome.
If allowed to multiply unchecked, these "jumping genes" can inactivate essential genes or activate cancer-causing genes. "In mice, you see the evolutionary hallmarks of the cells' struggle to keep these elements in check. Many existing copies of retrotransposons have been inactivated by APOBEC generated mutations," said Landau.
The tiny Adeno-associated virus depends on the help of the larger Adenovirus to multiply and does no harm in humans. "We think that a pathogenic virus that is like AAV could be the real target of 3A," said Weitzman. "One candidate might be parvovirus B19, which infects red blood cells and causes Erythema infectiosum (Fifth disease or 'slapped cheek syndrome') in children," he explained.
Unlike other members of the APOBEC family, A3A has no effect on HIV or other retroviruses. "One explanation could be that 3A appears to be active in the cell's nucleus where mobile elements and AAV multiply but the APOBEC-sensitive step during HIV replication happens outside the nucleus in the cytoplasm," speculates Landau.
Researchers who contributed to the work include co-first author Hui Chen and postdoctoral researchers Quin Yu and Jody Chou in the Infectious Disease Laboratory, co-first author Caroline E. Lilley as well as Darwin V. Lee and Iñigo Narvaiza in the Laboratory of Genetics.
The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.
Source: Salk Institute PR March 07, 2006
 APOBEC3A Is a Potent Inhibitor of Adeno-Associated Virus and Retrotransposons
Hui Chen, Caroline E. Lilley, Qin Yu, Darwin V. Lee, Jody Chou, Inigo Narvaiza, Nathaniel R. Landau, and Matthew D. Weitzman
Current Biology, Vol 16, 480-485, 07 March 2006
APOBEC3 proteins constitute a family of cytidine deaminases that provide intracellular resistance to retrovirus replication and transposition of endogenous retroelements . One family member, APOBEC3A (hA3A), is an orphan, without any known antiviral activity. We show that hA3A is catalytically active and that it, but none of the other family members, potently inhibits replication of the parvovirus adeno-associated virus (AAV). hA3A was also a potent inhibitor of the endogenous LTR retroelements, MusD, IAP, and the non-LTR retroelement, LINE-1. Its function was dependent on the conserved amino acids of the hA3A active site, consistent with a role for cytidine deamination, although mutations in retroelement sequences were not found. These findings demonstrate the potent activity of hA3A, an APOBEC3 family member with no previously identified function. They also highlight the functional differences between APOBEC3 proteins. The APOBEC3 family members have distinct functions and may have evolved to resist various classes of genetic elements.