Autophagy Shows Teeth in Self-Defense

Newswise — Cells give up their secrets slowly. Just when you think that all major cellular systems are understood, along comes a surprise. The latest is about autophagy, a major pathway for degrading and recycling within cells. The name comes from Greek words meaning "self" and "eating" , and was coined to describe how a cell facing starvation degrades its own components, especially proteins, to obtain nutrients for survival. Autophagy also helps in the normal 'turnover' of cellular constituents and organelles. New findings show that autophagy has pivotal roles not only in development and cell death, but also provides an innate 'second line of defense' against invading pathogens.

In work just published in Science, the laboratory of Tamotsu Yoshimori at Japan's National Institute of Genetics in Mishima and Ichiro Nakagawa and co-workers at Osaka University Graduate School of Dentistry report a new major role for autophagy—the elimination of invading pathogenic bacteria within cells. Autophagy involves the formation of unique double membrane structures called autophagosomes that can envelop portions of the cytoplasm and organelles. Eventually, autophagosomes fuse with lysosomes, enzyme- and acid-filled bags inside cells, to degrade their contents. Yoshimori and colleagues say that autophagosomes are used to capture invading bacteria that break through the cell's primary defenses.

The invader tested by Yoshimori was Group A Streptococcus (GAS), the ubiquitous bacterium that causes a range of human diseases including strep throat. (Certain strains of GAS have earned the grim nickname of "flesh-eating bacteria" ). GAS invades its host by the endocytosis pathway. The bacteria subvert the cell's primary defence system by engaging receptors that normally pick up cargo from outside the cell; these receptors and cargoes are normally taken into the cell within sealed 'endocytic' vesicles and are then sorted in endosomes for further use or sent to lysosomes for destruction. However once inside an endosome, GAS unleashes a toxin, the streptolysin O protein, to blow it open and escape into the cytoplasm. But not so fast, says Yoshimori. The autophagosomes are waiting in reserve.

In his experiment, Yoshimori first allowed GAS to infect cells as usual, via the endocytic Trojan horse. Just as GAS was blasting its way out of the endosome, the autophagy counterattack began. The autophagic machinery is highly specific, says Yoshimori, and can only recognize GAS that escapes from endosomes. Triggered by the presence of the escaped GAS, autophagosomes quickly formed and selectively sequestered the bacteria. To monitor the struggle, Yoshimori labelled the autophagosome membrane with a specific marker, LC3. The autophagosomes eventually fused with lysosomes where enzymes degraded and killed the GAS. Four hours after infection, the number of live GAS decreased to about 20 percent of their breakout numbers. The importance of autophagy in anti-bacterial defense was highlighted by studying cells defective in autophagy, due to the absence of a protein named ATG5. In these cells, GAS bacteria survived, multiplied, and spread out from its host cell to seek new victims.

Autophagic Machinery Provides a Cellular Defense System Against Invasion by a Pathogenic Bacteria, Group A Streptococcus, I. Nakagawa1,6, A. Amano2, N. Mizushima3, A. Yamamoto4, H. Yamaguchi5, T. Kamimoto5, A. Nara5, J. Funao1, M. Nakata1, K. Tsuda5, S. Hamada1, T. Yoshimori5, 7; Departments of 1Oral and Molecular Microbiology, and 2Oral Frontier Biology, Osaka University Graduate School of Dentistry, 3The Tokyo Metropolitan Institute of Medical Science, 4Nagahama Institute of Bio-Science and Technology, 5Department of Cell Genetics, National Institute of Genetics/SOKENDAI, 6PRESTO and 7CREST, Japan Science and Technology Agency

At the meeting: Session 235, Targeting to Lysomes, Poster Presentation #1170, Halls D/E. Author presents: Monday, Dec. 6., 1:30—3:00 PM.