The body's own recycling system: Researchers discover 'molecular emergency brake' in charge of regulating self-digestion

Using a microscope, the researchers are able to zoom in on the cells: If autophagy proceeds undisturbed, they are able to observe little digestive bubbles, shown in red, inside of which material is being degraded (left). If the final step is blocked, autophagosomes accumulate inside the cell, shown here in green (right). The dark circular area at the center is the nucleus. Credit: Ralf Höcker / HZI

Times of distress literally eat away at the core of starving cells: They start to digest their own parts and recycle them for metabolic purposes. Ingo Schmitz at the Helmholtz Centre for Infection Research in Braunschweig, Germany, together with a team of researchers, has discovered that a "molecular brake" is in charge of regulating autophagy to keep it from getting out of control. They published their findings in the scientific journal, Cell Death & Differentiation.

Almost everything that happens inside a cell, including autophagy, is tightly regulated on a biochemical level. Like that, the cell makes sure that processes only take place when they are needed and that they are shut off when the need has expired. "Inside the cell, there exists a network of molecules. Between them, information is constantly being exchanged," says Schmitz, head of the research group "Systems-oriented Immunology and Inflammation Research" at HZI, who also holds a chair at the Otto von Guericke University in Magdeburg. "In a way, it looks like a big city subway map." However, only the starting point and the destination of a given "cellular subway line" are relatively easy to study. To explore the different stops along the way, is more difficult. But because other lines intersect and interact with each other at these points, it is very exciting for researchers to decode all molecules involved in these signal transduction processes. It also helps them better understand diseases caused by defects in these information highways.

What exactly happens on a molecular level during the later stages of autophagy was largely unknown – until now. Schmitz and his team, along with researchers from the Otto von Guericke University Magdeburg, the Heinrich Heine University Düsseldorf, the Tübingen University, and the Temple University School of Medicine in Philadelphia, USA, have decoded one part of the molecular subway map.

Under the microscope, researchers can observe how larger-sized cellular components destined for degradation and recycling are enclosed within a small bubble, the so-called autophagosome. This structure then fuses with yet another little bubble, which digests the autophagosome's contents. "Autophagy is a survival mechanism to ensure that the cell is able to obtain the necessary nutrients during times of starvation," explains Schmitz.

For their studies, the scientists stained certain molecules and autophagosomes inside cells. This allowed them to observe microscopically which molecules are in charge of regulating the formation of the little digestive bubbles. To prompt self-digestion, they either starved the cells or simulated an infection. In the process, they discovered that the cells simultaneously also turned on autophagy-inhibiting molecules – "like some kind of emergency brake that ensures autophagy doesn't get out of control." Such negative feedback loops are not unusual for , they frequently help prevent overshooting reactions.

The researchers managed to identify the components of this feedback loop and found a protein called p38 to play a key role in the process. The scientists were especially surprised to observe p38 proteins on the surface of the autophagosomes. Normally, this protein is localized inside the nucleus where it gets switched on whenever the cell is under stress. On the surfaces of autophagosomes, p38 performs a very different job: It alters another molecule, called Atg5, to get it to block the final step of autophagy, involving formation of the little digestive bubble. Autophagy is inhibited, and, essentially, the cell pulls the "molecular emergency brake."

If it didn't, diseases could potentially result. As such, defective molecules of the Atg family have been implicated in the etiology of the inflammatory bowel disease, Morbus Crohn. "Looking at Atg5-deficient mice, which die of nutrient-deficiency shortly after they are born, we see just how important it is to tightly regulate ," emphasizes Ralf Höcker, one of the study's first authors. As so often, it is important to find the right balance, in this case, between too much and too little self-digestion.

More information: Eric Keil, Ralf Höcker, Marc Schuster, Frank Essmann, Nana Ueffing, Barbara Hoffman, Dan A. Liebermann, Klaus Pfeffer, Klaus Schulze-Osthoff, Ingo Schmitz Phosphorylation of Atg5 by the Gadd45b-MEKK4-p38 pathway inhibits autophagy Cell Death & Differentiation, 2012 doi:10.1038/cdd.2012.129

Provided by Helmholtz Centre for Infection Research

5 /5 (2 votes)
add to favorites email to friend print save as pdf

Related Stories

Protein identified that can lengthen our life?

Feb 27, 2012

Cells use various methods to break down and recycle worn-out components—autophagy is one of them. In the dissertation she will be defending at Umea University in Sweden, Karin Håberg shows that the protein SNX18 ...

Cell recycling protects tumor cells from anti-cancer therapy

Mar 06, 2008

Cells have their own recycling system: Discarded cellular components, from individual proteins through to whole cellular organs, are degraded and the building blocks re-used in a different place. The scientific term for this ...

Self-digestion as a means of survival

Feb 27, 2009

In times of starvation, cells tighten their belts: they start to digest their own proteins and cellular organs. The process - known as autophagy - takes place in special organelles called autophagosomes. It is a strategy ...

Recommended for you

Gene mutation discovered in blood disorder

10 minutes ago

An international team of scientists has identified a gene mutation that causes aplastic anemia, a serious blood disorder in which the bone marrow fails to produce normal amounts of blood cells. Studying a family in which ...

Airway muscle-on-a-chip mimics asthma

2 hours ago

The majority of drugs used to treat asthma today are the same ones that were used 50 years ago. New drugs are urgently needed to treat this chronic respiratory disease, which causes nearly 25 million people ...

Lost protein could prevent hardening of the arteries

6 hours ago

(Medical Xpress)—Researchers have found that when the protein matrix metalloproteinase-14 (MMP-14) is reduced or lost, white blood cells, known as macrophages, become good and could prevent hardening of ...

User comments