visual image

News & Publications

Bertozzi, Keasling and co-workers discover clues to TB virulence

Phagocytosis
Phagocytosis is the process by which a macrophage type white blood cell engulfs a bacterium in a membrane-bound shell called a phagosome. The phagosome fuses with a lysosome which carries digestive enzymes that destroy the bacterium. (Image by Flavio Robles, Berkeley Lab Public Affairs-CSO)

(Based on a Lawrence Berkeley National Laboratory press release by Lynn Yarris)

A link between the immune system and the self-cleaning system by which biological cells rid themselves of obsolete or toxic parts may one day yield new weapons in the fight against tuberculosis and other deadly infectious diseases.

Two College of Chemistry professors, Carolyn Bertozzi (the T.Z. and Irmgard Chu Distinguished Professor of Chemistry) and Jay Keasling (the Hubbard Howe Jr. Professor of Biochemical Engineering) and co-workers have discovered proteins residing in both systems that point to "cross-talk" between them. "It's like discovering your vacuum cleaner has been giving orders to your home alarm system," says Bertozzi.

When bacteria or other foreign particles invade the body, the first defenders are white blood cells called macrophages, which engulf and contain the invaders within the membrane-bound shells of their phagosomes. Once safely contained, the invaders can be killed with digestive enzymes from another cell organelle, called a lysosome.

Macrophages, like other kinds of cells, also use lysosomal enzymes for internal housekeeping. However, until now there has been no direct biochemical evidence of a link between phagocytosis (capturing and destroying the invaders) and autophagy (vacuuming up cellular waste).

In collaboration between the two research groups, profiles were obtained for 546 different types of proteins in the membrane of a phagosome, an organelle of macrophages that essentially "eats" and destroys invading organisms.

"We were able to identify many new proteins that were not previously known to reside in the phagosome," said Wenqing Shui, a member of both the Bertozzi and Keasling research groups, and a proteomics specialist who was the lead author on a paper reporting these results in the Proceedings of the National Academy of Sciences.

"One of the new proteins exclusively found in our study, LC3-II, is considered a marker of autophagy, the process that enables cells to clean up their own cytoplasm," Shui said. "Not only was LC3-II present in the phagosome, its level was increased upon the induction of autophagy in macrophages, and reduced when autophagy was suppressed. This indicates cross-talking between autophagy and phagocytosis that may play an important role in the response of the immune system."

Shui explains that the bacterium that causes tuberculosis may be able to silence this communication, allowing TB bacteria to lurk unnoticed inside the macrophage. "After tuberculosis bacteria are phagocytosed into the macrophage cell, they are able to subvert various host defense mechanisms,"she says, "including the killing of bacilli in the phagosome, and survive well inside the cell."

The Bertozzi and Keasling research groups are now examining whether certain mycobacterial products can modulate macrophage autophagy activity. They are also looking for proteins that could specifically mediate the autophagy as well as the phagosome maturation process.

Said Shui, "We might be able to open new avenues for discovering drugs to help control tuberculosis and other infectious diseases."

Bertozzi is the director of Lawrence Berkeley National Laboratory (LBNL) Molecular Foundry nanoscience center, and Keasling is director of LBNL Physical Biosciences Division. In addition, Bertozzi is an investigator with the Howard Hughes Medical Institute, and Keasling is director of the Joint BioEnergy Institute.

The PNAS paper is entitled: "Membrane proteomics of phagosomes suggests a connection to autophagy." Co-authoring this paper in addition to Shui, Bertozzi and Keasling were Leslie Sheu, Jun Liuc, Brian Smart, Christopher Petzold, Tsung-yen Hsieh and Austin Pitcher.

This research was supported by grants from the National Institutes of Health and the U.S. Department of Energy's Genomics:GTL program.

[top of page]