Sci. Aging Knowl. Environ., 28 September 2005
Suicide-squelching molecule also slows cellular cannibalism
The protein Bcl-2 performs cellular interventions, preventing hard-pressed cells from killing themselves. New research shows that this molecular rescuer also stops cells from gobbling their own contents. The work clarifies how hungry cells control recycling of their raw materials.
When times get tough, a cell often digests part of its innards, a process called autophagy (see Cuervo Perspective). Self-consumption not only allows reuse of nutrients but also eliminates damaged molecules. Autophagy slows with age (see "Picky Eater"), and its decline could allow the buildup of abnormal proteins in neurodegenerative diseases (see "Stuck in the Craw"). Some evidence suggests that autophagy promotes apoptosis, or programmed cell death. The two processes share molecular machinery, and recent studies have revealed another possible connection: A protein called Beclin 1, which helps orchestrate autophagy, latches onto Bcl-2, a protein that impedes apoptosis. Molecular biologist Beth Levine of the University of Texas Southwestern Medical Center in Dallas and colleagues wanted to determine whether the two molecules work together to control autophagy.
The researchers first measured autophagy in starving yeast cells lacking their version of Beclin 1. Fewer than 30% of these cells performed autophagy. Altering the yeast to produce Beclin 1 tripled that percentage. When the team prodded the Beclin 1-making cells to fashion more Bcl-2, the amount of self-eating plunged. The researchers then engineered yeast to manufacture a Beclin 1 version that won't bind to Bcl-2. About 70% of these cells showed signs of autophagy, and cranking up Bcl-2 production didn't reduce that value. Together, those experiments suggest that the two proteins collaborate to inhibit autophagy, says Levine.
The team then studied human cells that fashion both proteins. When the cells were hungry, Bcl-2 barely stuck to Beclin 1, but the proteins readily hooked up when food was abundant. The findings suggest that busting up the Beclin 1-Bcl-2 tandem turns on autophagy when cells need food, Levine says. A further experiment on cells that lack Beclin 1 showed that reining in autophagy is important for keeping cells alive. Modifying the cells to pump out Beclin 1 that rebuffs Bcl-2 hikes the amount of autophagy--and boosts the rate of cell death. The team's findings contradict a 2004 Japanese study, which found that Bcl-2 stimulates autophagy in mouse connective tissue cells. The reason for the discrepancy isn't clear, says Levine, but one possible explanation is that Bcl-2 works differently in different tissues.
The work elegantly demonstrates Bcl-2's role in turning down autophagy, says cell biologist Ana Maria Cuervo of Albert Einstein College of Medicine in New York City. Scientists have been dueling over whether self-consumption is good or bad for cells, she says, and the study backs the notion that moderate amounts of autophagy are beneficial. Too much can trigger cells to perish, but too little can leave them short of nutrients. Researchers now need to focus on whether Bcl-2 contributes to autophagy's slowdown with age, she adds. That work could reveal whether Bcl-2 lets cells down as we get older.
September 28, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150