Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Intracellular transport New portals of entry into cells for pathogenic agents and for medicinal products

06.12.2007
How does the cell membrane capture pathogenic agents bound to its surface?

Surprisingly, the membrane invaginates through a spontaneous and autonomous movement and swallows pathogens. This mechanism has been demonstrated in cells, and also in a minimal artificial membrane system. An international collaboration between physicists, including Patricia Bassereau and her CNRS team, chemists, and cell biologists at the Institut Curie, has observed this process at work with a particular pathogen, Shiga toxin.

The work has been done by Ludger Johannes, Research Director at Inserm, and his CNRS Trafficking, Signaling, and Delivery team, using the Institut Curie’s imaging equipment. The results shed new light on unexpected aspects of a fundamental process in biology—endocytosis(1). They also point to new leads in the search for the portal of entry of certain pathogenic agents, or to expedite the entry of drugs, therapeutic vaccines, or diagnostic agents in cancer cells. This work was published online in Nature of 29 November 2007.

Like in cartoons depicting how the inhospitable jungle magically opens before an intruder only to close behind him as he passes on his way, the cell membrane acts similarly when it spontaneously invaginates on contact with certain pathogenic agents. The membrane has no need of magic or trickery, just the laws of physics, as shown at the Institut Curie by a group of researchers working on Shiga toxin, a pathogenic agent produced by intestinal bacteria (see references and box). Shiga toxin clutches several receptors along its way, drawing an “islet in the ocean of the membrane”, according to Winfried Römer, a young post-doc in the team of Ludger Johannes(2). This islet forms a depression to produce a sort of “finger”, or tubule, pushing into the cell. The tubule is then cut off by the cellular machinery and internalized.

This discovery may seem trivial to the uninitiated, but in fact represents an important conceptual advance, which casts new light on endocytosis. This mechanism allows large molecules and particles, generically called “cargos” (extracellular ligands, nutrients, viruses, bacteria, toxins) to enter the cell in endocytotic vesicles, as if in a Trojan horse. Current data suggest that the cargo reaches a predetermined platform before being taken over by the cell, using energy in the process and with the help of proteins, one of which, clathrin, constructs a coat that presses into the membrane the shape of an empty cage. This cage closes around the membrane vesicle containing the cargo, which is internalized in the cell. The endocytotic vesicles then fuse with the endosomes, which are intracellular compartments enabling the sorting of internalized molecules. These molecules then meet various fates: return to the plasma membrane (recycling), degradation, transfer to other intracellular compartments (Golgi apparatus, endoplasmic reticulum, etc). It has been recognized, however, that this clathrin-dependent pathway of endocytosis is not unique. Indeed, researchers have observed before that some cargos, like Shiga toxin, are captured by other, as yet unspecified mechanisms.

After more than three years of research at the Institut Curie, the scientists have discovered a new method of access to the cell that does not involve cell proteins like clathrin. The mechanical forces imposed on the membrane, in this case by Shiga toxin, are enough to trigger its invagination.

Using various techniques to suppress at will the cell’s energy or certain molecules (actin, dynamin...), the researchers were able to identify how the membrane invaginates and forms tubules, in response to the binding of the B-subunit of Shiga toxin: this part of the molecule has specific receptors in the cell membrane, the Gb3 glycolipid. The invagination is spontaneous, but highly selective: the tubules were not formed when the researchers replaced the B-subunit by a decoy.

The CNRS team of physicists headed by Patricia Bassereau at the Institut Curie has reproduced this mechanism in an original system: a made-to-measure artificial lipid bilayer modeled on the plasma membrane. When the B-subunit of Shiga toxin is put in contact with this giant vesicle of 10 to 30 micrometers in diameter, they form intense spots, from which the tubules form. As expected, neither spots nor tubules are formed when the membrane is devoid of the right receptors. Using receptor variants synthesized by chemists in Jean-Claude Florent’s CNRS group, the researchers tested and verified another much more groundbreaking hypothesis: that the Gb3 receptor is itself implicated in the invagination. Each B-subunit grips up to 15 receptors, whose bulky lipid tails form the wide base of a cone. “Our artificial membrane system is the key manipulation showing, and we have images to back this up, that the invagination needs no energy or cellular components to occur. Only the concentration of toxins closely bound to their receptors creates microdomains with depressions in the membrane that accumulate and end up forming a tubule”, summarizes Winfried Römer.

This discovery points to new concepts about endocytosis. This purely physical mechanism may apply to cargos other than Shiga toxin, notably certain viruses. Ludger Johannes has said that “the membrane is more active than we thought, and even when clathrin intervenes, it perhaps organizes microdomains rather than scaffolding the membrane into cage-like structures.” This could lead on to new strategies in the fight against infections, poisonings, and cancers, by, for instance, targeting the membrane lipids, which are still poorly understood. This is how Institut Curie researchers, headed by Ludger Johannes, use the B-subunit of Shiga toxin to transport antigens inside certain immune cells to trigger an anti-tumor or antiviral immune response. Similarly, the same transporter can target and selectively destroy cancer cells.

Note
(1) Mechanism whereby the cell membrane invaginates and internalizes large molecules.

(2) UMR 144 – CNRS/Institut Curie – « Traffic, signaling and delivery » team..

Catherine Goupillon | alfa
Further information:
http://www.nature.com/nature/index.html

Further reports about: B-subunit CNRS Entry Ludger Pathogen Shiga invaginates pathogenic receptor tubule vesicle

More articles from Life Sciences:

nachricht Symbiotic bacteria: from hitchhiker to beetle bodyguard
28.04.2017 | Johannes Gutenberg-Universität Mainz

nachricht Nose2Brain – Better Therapy for Multiple Sclerosis
28.04.2017 | Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik IGB

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Fighting drug resistant tuberculosis – InfectoGnostics meets MYCO-NET² partners in Peru

28.04.2017 | Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

 
Latest News

Wireless power can drive tiny electronic devices in the GI tract

28.04.2017 | Medical Engineering

Ice cave in Transylvania yields window into region's past

28.04.2017 | Earth Sciences

Nose2Brain – Better Therapy for Multiple Sclerosis

28.04.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>