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Cell biology and
metabolism branch
Juan Bonifacino, PhD,
Chief The Cell Biology and Metabolism Branch (CBMB)
conducts studies in various areas of molecular cell biology, including the
mechanisms of intracellular protein trafficking and organelle biogenesis, iron
metabolism, adaptive responses to environmental stresses, and regulation of
the cell cycle during oogenesis. The CBMB’s outstanding microscopy
facilities permit the use of state-of-the-art techniques such as fluorescent
imaging of cells in real time, photobleaching, fluorescence resonance energy
transfer, fluorescence correlation spectroscopy, and image analysis in the
study of cell structure and dynamics. In addition, the CBMB is equipped with
facilities for work with many model organisms, including bacteria, yeast, Drosophila melanogaster, mice, and mammalian cells. Members of the
CBMB apply knowledge gained from the study of basic cell-biological problems
to the elucidation of the causes of human diseases, including disorders of
lysosome-related organelles, iron overload, and viral pathogenesis. Over the past year, the Section on Intracellular Protein Trafficking, led by Juan Bonifacino,
discovered critical components of the molecular machinery involved in the
exchange of materials between cells and their environment. In particular, the
group has contributed to the identification of proteins that determine
transport of molecules to endosomes and lysosomes. Among the identified
components are novel protein complexes that are defective in mouse models of
Hermansky-Pudlak syndrome, a pigmentation and bleeding disorder. In addition,
the group has discovered that defective protein biogenesis in the endoplasmic
reticulum (ER) underlies another genetic disorder, autosomal dominant
polycystic liver disease. Ramanujan Hegde’s
group, the Unit on Protein Biogenesis,
discovered a novel site of cellular regulation, the translocation of
secretory and membrane protein substrates into the mammalian ER. During the
past year, the group elucidated several examples of regulated protein
translocation that affect both normal physiology and disease progression. In
one particularly noteworthy example, the researchers found that the
generation of potentially neurotoxic forms of the prion protein was
controlled during its translocation into the ER. The consequence of
misregulating prion protein translocation for the development of
neurodegeneration is now under investigation in transgenic mouse model
systems recently developed by the group. Catherine Jackson’s
group, the Unit on GTPase Regulation of
Membrane Traffic, identified interacting partners of activators (GEFs) of
the Arf GTPase, a central regulator of organelle structure and function in
eukaryotic cells. In particular, she has identified the Golgi-localized,
vesicle-tethering complex TRAPPII as a direct partner of the Gea2p GEF.
TRAPPII is also an effector of Arf; hence the interactions demonstrate
coordination of the events of vesicle budding and vesicle fusion within the
Golgi apparatus. This and other interactions are shedding new light on the
mechanisms of trafficking through the secretory pathway that are conserved
throughout eukaryotic evolution. Mary Lilly’s
group, the Unit
on Cell Cycle Regulation, studies cell cycle regulation during gametogenesis.
Over the last year, the group characterized a highly conserved gene, mio, that provides a link between the
response to DNA damage and meiotic progression. In addition, the group has
explored how mitotic quiescence is maintained during meiosis and discovered a
unique role for translational repression. These studies have provided novel
insights into the relationship between early meiotic progression and oocyte
development. Jennifer Lippincott-Schwartz’s
group, the Section on Organelle Biology,
has continued to use novel fluorescence imaging tools, including
multispectral time-lapse imaging, photobleaching, and photoactivation, to
investigate many important cellular processes, such as cell division, protein
secretion, organelle transformation, and the mechanism for raft formation at
the plasma membrane. Her group recently discovered that the behavior of
chromosomes, cytoskeleton, and Golgi during mitosis is coordinated through
the activity of the small GTPase Arf1; that organelles are capable of transforming
from reticular networks into tightly stacked arrays through low-affinity
protein-protein interactions; that proteins residing within raft domains at
the plasma membrane undergo rapid partitioning in and out of these domains;
and that delivery of raft-associated proteins to apical surfaces of polarized
cells occurs by an indirect rather than direct route. Tracey Rouault’s
group, the Section on Human Iron
Metabolism, studies the regulation of iron metabolism. The group
discovered that an iron exporter known as ferroportin is present in synaptic
vesicles and that the iron storage protein ferritin is transported into
neuronal axons. Unusual iron distribution and trafficking patterns may
explain why neurons are unusually susceptible to damage when iron metabolism
is misregulated. These discoveries may promote understanding of
neurodegenerative diseases, especially Parkinson’s disease. Gisela
Storz’s group, the
Section on Environmental Gene Regulation, has continued its studies on
the mechanisms by which cells defend against oxidative stress, including
analyses of key regulators of the cellular responses to hydrogen peroxide in
bacteria and yeast. Another area of research is the identification and
characterization of untranslated, regulatory RNAs. Systematic screens for
noncoding RNA genes in E. coli
resulted in the identification of more than 30 new noncoding RNAs whose
functions are now under investigation. |