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RESEARCH BRIEFS
Herpes Oncovirus Reveals Trick for Dodging Immune SystemAll herpesviruses have some way of downregulating the key immune surveillance molecule, class I major histocompatibility complex (MHC I), but nothing delights a herpes virologist more than discovering yet another way the bugs evade the immune system. Working with the human herpes oncovirus, Kaposi's sarcoma-associated herpesvirus (KSHV), researchers at the New England Regional Primate Research Center have found a new trafficking mechanism enabling the virus to give the immune system the slip (see image below).
Immune distress signals: now you see them, now you don't. Researchers in the tumor virology laboratory of Jae Jung, HMS associate professor of microbiology and molecular genetics at the New England Regional Primate Research Center, have discovered a new mechanism used by the Kaposi's sarcoma-associated herpesvirus (KSHV) to evade cytotoxic T lymphocytes. As fast as an infected cell can signal an immune alarm by packing viral proteins onto MHC class I molecules and pushing them out to the cell surface, K3 and K5 proteins made by the virus pull the signaling molecule back inside the cell and send it first to the Golgi complex and then to the lysosome for dismantling. (Illustration adapted from original by Robert Means) Normally, viral peptides presented by MHC I molecules on an infected cell alert immune forces to kill the cell and recruit reinforcements to kill more cells that are similarly infected. But KSHV makes two proteins, K3 and K5, that counter this immune strategy. As fast as an infected cell can push out MHC I distress signals, the two proteins cause the cell to grab the molecules back inside, sending them first to the Golgi complex and then to the lysosome for destruction. The researchers documented this new endocytosis mechanism using fluorescent microscopy of human B cells and endothelial cells expressing the KSHV proteins. "The key to herpes' persistence is the ability to keep the immune system at bay," said HMS instructor in microbiology and molecular genetics Robert Means, who shares a first author credit on the April 1 EMBO Journal paper. KSHV is believed to be the main cause of Kaposi's sarcoma, the most common AIDS-related neoplasm and a leading cause of cancer deaths in Africa. It also is linked to two other cancers, primary effusion lymphoma and plasmablastic multicentric Castleman's disease. Unpublished data presented at recent scientific meetings suggest increasing seroprevalence. Despite the enigma of the virus's epidemiology, it seems to cause cancer only in immunosuppressed people, elderly people, and those with susceptible genetic backgrounds.
Fishing for Good HealthDining often on fish--especially dark, fatty types such as salmon or mackerel--is a habit that can dramatically lower a person's risk of heart disease and heart attack, according to a pair of studies appearing this month by Harvard School of Public Health and Brigham and Women's Hospital researchers. Frank Hu and colleagues studied 85,000 women and found that those who ate fish two to four times a week had a 31 percent lower chance of developing coronary heart disease than those who ate fish less than once a month. Those who ate fish five or more times a week reduced their risk by 34 percent--and they cut their chances of suffering a heart attack by half. Hu, HSPH assistant professor of nutrition and cardiovascular disease, and colleagues report their findings in the April 10 Journal of the American Medical Association. Previous studies have shown that eating fish lowers the risk of coronary heart disease in men, but this is the first to show that finned foods work their protective magic in women. Men were recently evaluated for a different type of heart disease, namely sudden heart attack. This class of coronary disease is due to disturbances in the heart's rhythmic beating. Christine Albert and her colleagues at BWH studied blood levels of omega-3 fatty acids--a substance prevalent in fish, especially the dark, fatty kinds mentioned above--in men with no prior history of cardiovascular disease. Those with the highest levels were more than 80 percent less likely to die from sudden heart attack, the researchers report in the April 11 New England Journal of Medicine.
Dopamine Receptor Puts Brake on Self-DestructionDopamine is a jack-of-all-trades neurotransmitter, acting as a messenger for motor, sensory, and motivational behaviors. Dopamine's versatility is due to its ability to bind five different receptor subtypes, each of which triggers a different molecular cascade inside the postsynaptic cell. One strategy for treating dopamine-related illnesses such as Parkinson's disease, schizophrenia, and ADHD is to target just one dopamine subtype. Yet researchers' efforts to single out dopamine receptors have been thwarted by a lack of knowledge about how one receptor subtype functions differently from the others. Barak Caine, HMS assistant professor of psychology at McLean Hospital, and his colleagues have begun to separate one of these subtypes from the crowd, the D2 receptor. In the April 1 Journal of Neuroscience, they report that the D2 receptor is involved in a rodent's ability to limit the amount of drug it takes in. The researchers found that when mice lacking the D2 receptor were given the opportunity to self-administer high doses of cocaine, they did so at a faster rate than wild type mice. So impaired was their internal braking system that the first three knockouts overdosed. Caine and his colleagues found similar behavior in intact rats whose D2 receptors were chemically blocked. Intriguingly, differences in self-limiting behavior were not observed when animals were offered low doses of cocaine. Caine believes that it is only at higher doses, which carry the danger of an overdose, that the braking system kicks in and the effects of lacking a functional D2 may show up. How the D2 receptor works is not clear; it could induce excessive intoxication, debilitating motor effects, or satiation, Caine said.
How the Cell Decommissions ProteinsThe pinning of phosphate groups to proteins is one of the most well-studied processes in the cell, and for good reason. Phosphorylation is the means by which the cell activates proteins to perform their various missions. How these phosphate badges are removed--where, when, and by what cellular agents--after a protein's job is done is a generally less well-understood puzzle. The fact that a popular candidate for the role of dephosphorylating agent resides deep inside the cell, on the endoplasmic reticulum, only adds to the mystery. This enzyme, protein tyrosine-phosphatase-1B (PTP1B), is thought to dephosphorylate proteins residing in far-flung locations--on the plasma membrane or in membrane-bound vesicles. How might PTPB1 interact with these distant or closeted proteins from its perch on the ER? The answer, it appears, is that the proteins are delivered to it. Using methods for imaging protein interactions, Fawaz Haj, Benjamin Neel, and colleagues in Germany followed two cell surface proteins, the receptors for epidermal growth factor (EGF) and for platelet-derived growth factor (PDGF). Once activated, they report in the March 1 Science, the proteins were essentially swallowed into vesicles and ferried to the endoplasmic reticulum, where they interacted with the phosphate-stripping region of PTP1B. What has made this relationship so elusive until now is that PTP1B is known to remove phosphates from activated proteins too quickly to be seen. To visualize the interaction, Haj, HMS research fellow in medicine; Neel, HMS professor of medicine, both at Beth Israel Deaconess; and colleagues engineered a cell with a mutant PTP1B, one that holds onto activated proteins rather than stripping them of their phosphate groups. Sure enough, activated proteins, labeled with green fluorescent protein, and PTPB1, tagged with monoclonal antibodies, were seen to colocalize to the ER. In some diseases, receptors may be activated all the time. "Diseases like cancer and diabetes involve abnormal tyrosine phosphorylation, so a better understanding of how the EGF and PDGF receptors are dephosphorylated could lead to deeper insight into their disease mechanisms," Haj said. --Three briefs above by Misia Landau |
