Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

FMP and MDC Researchers Identify a Fundamental Process in Lysosomal Function and Protein Degradation

16.06.2010
The degradation of proteins and other macromolecules in cells is vital to survival. Disruption of this process can result in serious disease.

The research group of Professor Thomas Jentsch (Leibniz Institute for Molecular Pharmacology, FMP/ Max Delbrück Center for Molecular Medicine, MDC, Berlin-Buch) has now succeeded in identifying an essential cellular process necessary for the transport and degradation of macromolecules in endosomes and lysosomes, respectively. In two studies published in the same issue of Science, they showed that contrary to scientific consensus the function of these cell organelles not only depends on the pH, but also on chloride ion accumulation in their interior.*

Proteins are the building blocks and machines of life. Tens of thousands of them are present in each cell, where they perform essential tasks for the organism. Once they have fulfilled their function, they must be degraded to avoid causing damage. One way in which proteins can be degraded is via the digestion processes inside tiny cellular organelles, the lysosomes. The transport of the proteins destined for degradation to these cellular “trash bins” is partly carried out by endosomes, which deliver proteins from the cell surface to the cell interior.

The functionality of both endosomes and lysosomes depends on the ion concentration within their membrane-enclosed interior. In particular, an important role is ascribed to a high concentration of hydrogen ions, i.e. an acidic pH, inside those organelles.

The two studies by Dr. Stefanie Weinert, Dr. Gaia Novarino and Professor Thomas Jentsch focus on two ion transport proteins, the chloride transporters ClC-5 and ClC-7. These are located in the membrane of endosomes and/or lysosomes and exchange negatively charged chloride ions for positively charged hydrogen ions (protons).

ClC-5 is located in the membrane of endosomes in renal cells. If ClC-5 is defective or lacking altogether, proteins can hardly be absorbed from the urine any longer. In a cascade of indirect mechanisms, this leads to the development of kidney stones in Dent’s disease.

ClC-7 is located in the membrane of lysosomes in all cells of the body. The research group by Thomas Jentsch showed already a few years ago that mutations of ClC-7 in mice and humans lead to severe disease symptoms. Impaired lysosomal function in the brain results in severe degenerative changes that leads to massive neuronal death. A dysfunction of bone-degrading osteoclasts causes an excessive calcification of bones (osteopetrosis).

The chloride-proton exchangers ClC-5 and ClC-7 function parallel to proton pumps, which ensures an acidic environment within endosomes and lysosomes. ClC-5 and ClC-7 transport chloride ions into these organelles, thereby electrically balancing the inward transport of positively charged protons through the “pump”. Hitherto researchers had assumed that maintaining the charge balance was the sole task of ClC-5 and ClC-7, without which both the transport of endosomes and lysosomal protein degradation are impaired.

However, Professor Jentsch and his team showed several years ago that the pH in lysosomes devoid of ClC-7 is normal and that nevertheless lysosomal storage disease and osteopetrosis ensue. This means that charge balancing in lysosomes may involve a different, previously unknown mechanism, and that the main task of ClC-7 may rather be the regulation of lysosomal chloride concentration. The Berlin research group proposed that the exchange of chloride for protons, which are more highly concentrated in the acidic environment of lysosomes than in the rest of the cell, accumulates chloride ions in lysosomes. A high lysosomal chloride concentration may be functionally important.

“In an elegant experimental approach” as Professor Jentsch explains the test of this hypothesis, “Dr. Novarino and Dr. Weinert converted the ClC-5 and ClC-7 chloride-proton exchangers in the mouse into pure chloride conductors (channels). They exchanged a single amino acid out of a total of around 800 present in the ion transporters”. These mutated transport proteins are optimally suited to compensate the charge transfer by the proton pump and therefore should, according to the hypothesis of the research group, support the acidification of the organelles very well.

On the other hand, the uncoupling of chloride transport from proton transport should significantly lower the accumulation of chloride into these organelles. Indeed, this prediction was confirmed experimentally in their mouse model. “Surprisingly,” Professor Jentsch said, “the corresponding mice showed almost the same disease symptoms as with a total lack of the respective proteins.”

With this experiment, the MDC and FMP researchers were able to show for the first time that not only the lack of endosomal/lysosomal acidification, but also a reduced accumulation of chloride ions in these organelles plays a crucial role in generating the severe symptoms of these hereditary diseases, that is a form of kidney stone disease as well as neurodegeneration. A dysregulation of organellar chloride concentration may also play a role in other human diseases.

*Science 11 June 2010, Vol. 328. no. 5984, pp. 1398-1401; DOI: 10.1126/science.1188070; originally published in Science Express on 29 April 2010
*Endosomal Chloride-Proton Exchange Rather Than Chloride Conductance is Crucial for Renal Endocytosis
Gaia Novarino1, Stefanie Weinert1, Gesa Rickheit1,2 & Thomas J. Jentsch1
1 Leibniz-Institut für Molekulare Pharmakologie (FMP)and Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany

2 Present address: TaconicArtemis GmbH, Köln, Germany

Science 11 June 2010, Vol. 328. no. 5984, pp. 1401-1403, DOI: 10.1126/science.1188072; originally published in Science Express on 29 April 2010; * Lysosomal Pathology and Osteopetrosis Upon Loss of H+-Driven Lysosomal Cl- Accumulation
Stefanie Weinert1,2, Sabrina Jabs1,2,6, Chayarop Supanchart3, Michaela Schweizer4, Niclas Gimber1,2, Martin Richter1,6, Jörg Rademann1,6,7, Tobias Stauber1,2,Uwe Kornak3,5 & Thomas J. Jentsch1,2
1 Leibniz-Institut für Molekulare Pharmakologie (FMP), Berlin, Germany
2 Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany
3 Institut für Medizinische Genetik, Charité Universitätsmedizin Berlin, Germany
4 Zentrum für Molekulare Neurobiologie (ZMNH), Universität Hamburg, Hamburg, Germany
5 Max-Planck-Institut für Molekulare Genetik, Berlin, Germany
6 Freie Universität, Berlin, Germany
7Present address: Institut für Pharmazie, Universität Leipzig, Leipzig, Germany
Barbara Bachtler
Press and Public Affairs
Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch
Robert-Rössle-Straße 10; 13125 Berlin; Germany
Phone: +49 (0) 30 94 06 - 38 96
Fax: +49 (0) 30 94 06 - 38 33
e-mail: presse@mdc-berlin.de

Barbara Bachtler | Max-Delbrück-Centrum
Further information:
http://www.mdc-berlin.de/

More articles from Life Sciences:

nachricht Water forms 'spine of hydration' around DNA, group finds
26.05.2017 | Cornell University

nachricht How herpesviruses win the footrace against the immune system
26.05.2017 | Helmholtz-Zentrum für Infektionsforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Can the immune system be boosted against Staphylococcus aureus by delivery of messenger RNA?

Staphylococcus aureus is a feared pathogen (MRSA, multi-resistant S. aureus) due to frequent resistances against many antibiotics, especially in hospital infections. Researchers at the Paul-Ehrlich-Institut have identified immunological processes that prevent a successful immune response directed against the pathogenic agent. The delivery of bacterial proteins with RNA adjuvant or messenger RNA (mRNA) into immune cells allows the re-direction of the immune response towards an active defense against S. aureus. This could be of significant importance for the development of an effective vaccine. PLOS Pathogens has published these research results online on 25 May 2017.

Staphylococcus aureus (S. aureus) is a bacterium that colonizes by far more than half of the skin and the mucosa of adults, usually without causing infections....

Im Focus: A quantum walk of photons

Physicists from the University of Würzburg are capable of generating identical looking single light particles at the push of a button. Two new studies now demonstrate the potential this method holds.

The quantum computer has fuelled the imagination of scientists for decades: It is based on fundamentally different phenomena than a conventional computer....

Im Focus: Turmoil in sluggish electrons’ existence

An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.

We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...

Im Focus: Wafer-thin Magnetic Materials Developed for Future Quantum Technologies

Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.

Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...

Im Focus: World's thinnest hologram paves path to new 3-D world

Nano-hologram paves way for integration of 3-D holography into everyday electronics

An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Marine Conservation: IASS Contributes to UN Ocean Conference in New York on 5-9 June

24.05.2017 | Event News

AWK Aachen Machine Tool Colloquium 2017: Internet of Production for Agile Enterprises

23.05.2017 | Event News

Dortmund MST Conference presents Individualized Healthcare Solutions with micro and nanotechnology

22.05.2017 | Event News

 
Latest News

How herpesviruses win the footrace against the immune system

26.05.2017 | Life Sciences

Water forms 'spine of hydration' around DNA, group finds

26.05.2017 | Life Sciences

First Juno science results supported by University of Leicester's Jupiter 'forecast'

26.05.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>