PNAS | May 6, 2008 | vol. 105 | no. 18 | 6503-6504
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THIS WEEK IN PNAS
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DEVELOPMENTAL BIOLOGY
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The waiting game
Within days of fertilization, primitive blood cells begin to circulate through the mammalian embryo and rapidly differentiate, but there is a lag in the time it takes to achieve the final step to a functioning cell. To complete their maturation, these erythrocytes must first expel their nucleus—a process that Joan Isern et al. investigated by tracking the developing cells. Previous research had found that primitive erythrocytes express adhesion molecules that play a role in the migration of circulating cells into the fetal liver. Because the fetal liver does not develop until midgestation, its hosting of the final differentiation step could explain the time lag to maturation. Using transgenic mouse embryos with fluorescently tagged erythrocyte nuclei, the authors found that large numbers of extruded nuclei are present in the fetal liver around the time that mature cells are released into the bloodstream. Macrophages in the fetal liver appear to digest the discarded nuclei. The importance of the fetal liver in the maturation of erythrocytes may help to explain the lag between the first appearance of primitive erythrocytes and their differentiation to functional form, the authors say. — T.H.D.
"The fetal liver is a niche for maturation of primitive erythroid cells" by Joan Isern, Stuart T. Fraser, Zhiyong He, and Margaret H. Baron (see pages 6662–6667)
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IMMUNOLOGY
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Inactivating a human protein blocks HIV
Inactivating a human protein can block many steps of the HIV replication cycle, suggesting a new target for antiretroviral drugs. Julie Readinger et al. found that interfering with the ITK protein had multiple protective effects against HIV. Inactivation of ITK by RNA interference or chemical inhibition made it more difficult for HIV to enter a cell, spread throughout a tissue culture, transcribe its genes, and assemble into a functional viral particle, according to the authors. ITK is normally involved in activating the immune system's T cells so they can attack foreign organisms; HIV similarly infects and commandeers T cells in order to replicate, compromising the entire immune system. Readinger et al. show that, without an active ITK protein, many of the pathways that HIV exploits were less functional, and viral replication was inhibited or slowed. Because HIV is also notoriously quick to develop drug resistance through gene mutation, the authors suggest that targeting ITK—a human gene that is potentially less sensitive to drug resistance—could provide a new pathway for HIV treatment. — P.D.
"Selective targeting of ITK blocks multiple steps of HIV replication" by Julie A. Readinger, Gillian M. Schiralli, Jian-Kang Jiang, Craig J. Thomas, Avery August, Andrew J. Henderson, and Pamela L. Schwartzberg (see pages 6684–6689)
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MICROBIOLOGY, GEOLOGY
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Lipid defense against reactive oxygen
Polycyclic terpenoids are geologically stable lipids nicknamed "molecular fossils" because they enable scientists to link ancient hydrocarbons with the lifeforms that produced them. Previous research has suggested that oxygen is necessary for the synthesis of some of these compounds, making them markers for atmospheric oxygen. Tanja Bosak et al. report a new polycyclic terpenoid produced by Bacillus subtilis and made up of three isomers of a single compound that confers resistance to reactive oxygen species (ROS). A family of squalene and oxidosqualene cyclases is known to produce polycyclic terpenoids (sterols and hopanoids) in bacteria. Although B. subtilis contains a gene sqhC that resembles a gene encoding a squalene cyclase, the bacterium produces neither sterols nor hopanoids. Because sqhC is activated upon sporulation, the authors extracted lipids from the spores of B. subtilis and examined the gene products by using mass spectrometry. They identified isomers of a novel five-ring compound that they collectively dub "sporulenes." In its two-gene operon, sqhC is followed by sodF, a superoxide dismutase that converts ROS into oxygen and hydrogen peroxide. This finding suggests that sporulenes may be components of an ROS defense. The authors also found that the spores of mutants lacking sqhC are less resistant to ROS, and they hope to understand how sporulenes may prevent ROS from crossing the cell membrane. — K.M.
"A polycyclic terpenoid that alleviates oxidative stress" by T. Bosak, R. M. Losick, and A. Pearson (see pages 6725–6729)
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PHYSIOLOGY
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Erythrocyte suicide
Eryptosis, the programmed cell death of nucleus-free erythrocytes, shares a signaling pathway with apoptosis, Michael Föller et al. report. During eryptosis, a rise in intracellular calcium triggers exposure of phosphatidylserine to the external cell membrane, after which macrophages digest the erythrocytes. In nucleated cells, apoptosis is inhibited by NO via a pathway involving cyclic GMP and cGMP-dependent protein kinase type I (cGKI). Erythrocytes also possess a NO/cGMP pathway. To explore the influence of this pathway and cGKI on erythrocyte survival, the authors generated and characterized a cGKI knockout mouse model. These mice rapidly developed anemia and enlarged spleens, but the health of the strain was poor because cGKI expression appears to be crucial in smooth muscle. Conventional knockouts suffer from gastrointestinal dysfunction. The authors, therefore, generated a second knockout line in which cGKI expression was enabled only in smooth muscle. These mice also developed anemia and enlarged spleens, which contained large numbers of erythrocytes that displayed the molecular markers of eryptosis. In vitro experiments on erythrocytes from knockout and wild-type mice indicated that cGKI was active in erythrocytes. The authors suggest that cGKI reduces intracellular calcium and thus inhibits the exposure of phosphatidylserine. — K.M.
"Anemia and splenomegaly in cGKI-deficient mice" by Michael Föller, Susanne Feil, Kamran Ghoreschi, Saisudha Koka, Andrea Gerling, Martin Thunemann, Franz Hofmann, Beat Schuler, Johannes Vogel, Bernd Pichler, Ravi S. Kasinathan, Jan P. Nicolay, Stephan M. Huber, Florian Lang, and Robert Feil (see pages 6771–6776)
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Related articles in PNAS:
- The fetal liver is a niche for maturation of primitive erythroid cells
- Joan Isern, Stuart T. Fraser, Zhiyong He, and Margaret H. Baron
PNAS 2008 105: 6662-6667.
[Abstract]
[Full Text]
- Selective targeting of ITK blocks multiple steps of HIV replication
- Julie A. Readinger, Gillian M. Schiralli, Jian-Kang Jiang, Craig J. Thomas, Avery August, Andrew J. Henderson, and Pamela L. Schwartzberg
PNAS 2008 105: 6684-6689.
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[Full Text]
- A polycyclic terpenoid that alleviates oxidative stress
- T. Bosak, R. M. Losick, and A. Pearson
PNAS 2008 105: 6725-6729.
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[Full Text]
- Anemia and splenomegaly in cGKI-deficient mice
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PNAS 2008 105: 6771-6776.
[Abstract]
[Full Text]
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