Scientists discover that host cell lipids facilitate bacterial movement

When the bacterium Listeria monocytogenes invades the body, it commandeers its host cell's actin cytoskeleton to invade
other cells. In a report published in the Journal of Biological Chemistry, a group of scientists provide insight into the
molecular mechanisms behind this infection technique.


The research appears as the "Paper of the Week" in the March 25 issue of the Journal of Biological Chemistry, an American
Society for Biochemistry and Molecular Biology journal.


Listeria causes a variety of diseases, the most severe being meningoencephalitis, an inflammation of the brain and the
membranes that envelop the brain and spinal cord. Infection begins when the bacterium binds to a receptor on the surface of a
cell, causing the cell to ingest it. The bacterium multiplies inside the cell and then uses a cellular protein called ActA to
stimulate the host cell's actin to form filaments at one end of the bacterium.


"As these filaments lengthen, they drive the bacterium through the cell until it reaches the peripheral or outer cell
membrane," explains Dr. Frederick Southwick of the University of Florida College of Medicine. "Here the growing actin
filaments push the bacterium against the membrane, forming long membrane projections called filopodia. These filopodia push
into adjacent cells and are ingested by them. The bacteria then enter the new cell and begin the cycle anew. Essentially
Listeria takes over or hijacks the host cell's actin cytoskeleton to move within cells, and to spread from cell to cell."



In most cells, two membrane lipids, PIP2 and PIP3, are associated with the formation of new actin filaments. PIP3 is
synthesized from PIP2 by an enzyme called PI3-kinase. The lipids attract and modify the functions of proteins involved in
regulating actin assembly. PIP2 and PIP3 also prevent capping proteins from binding to the ends of actin filaments, allowing
new actin filament assembly.


Because Listeria is capable of stimulating actin assembly and PIP2 and PIP3 are known to localize to regions of new actin
assembly, Dr. Southwick and his colleagues decided to explore the roles these lipids play in Listeria infection.


"We had expected to see PIP2 and PIP3 only at the very back of Listeria where new actin assembly was taking place," recalls
Dr. Southwick. "To our surprise these lipids also localized to the front of the moving bacteria." The researchers also
noticed that Listeria movement slowed down when the bacteria were treated with molecules that inhibited PI3-kinase, proving
that Listeria depend on PI3-kinase to move.


"Our studies show that Listeria is capable of inside-out signaling," explains Dr. Southwick. "Most signals arise from
molecules binding receptors on the outside of the cell. In the case of Listeria, we find that this intracellular pathogen can
harness signals from the inner rather than the outer surface of the cell membrane.















"The most exciting and surprising finding is that an intracellular bacteria is able to attract host cell membrane lipids to
its surface and these membrane lipids facilitate the ability of the bacterium to move within cells. This capability is unique
to Listeria and is not found in another intracellular bacteria, Shigella. Our experiments show that Listeria is a simplified
model system for studying how phosphoinositides regulate the actin cytoskeleton, and this model promises to yield additional
insights into how these phospholipids control the cell's actin cytoskeleton. Our discoveries provide additional fundamental
clues as how cells move."


These findings may also open the door to using PI3-kinase inhibitors or other agents that lower PIP2 and PIP3 levels to slow
the spread of Listeria and control infection in patients who are not responding to antibiotics, although that application is
a long way off, says Dr. Southwick.


The Journal of Biological Chemistry's Papers of the Week is an online feature which highlights the top one percent of papers
received by the journal. Brief summaries of the papers and explanations of why they were selected for this honor can be
accessed directly from the home page of the Journal of Biological Chemistry online at jbc.


The American Society for Biochemistry and Molecular Biology (ASBMB) is a nonprofit scientific and educational organization
with over 11,000 members in the United States and internationally. Most members teach and conduct research at colleges and
universities. Others conduct research in various government laboratories, nonprofit research institutions, and industry.



Founded in 1906, the Society is based in Bethesda, Maryland, on the campus of the Federation of American Societies for
Experimental Biology. The Society's primary purpose is to advance the sciences of biochemistry and molecular biology through
its publications, the Journal of Biological Chemistry, The Journal of Lipid Research, Molecular and Cellular Proteomics, and
Biochemistry and Molecular Biology Education, and the holding of scientific meetings.


For more information about ASBMB, see the Society's website at asbmb.


Contact: Nicole Kresge

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301-634-7415

American Society for Biochemistry and Molecular Biology

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