2009/07/21
Necrotic serpin, the protein that checks fungal growth.
A group of researchers from CIC bioGUNE and the Andalusian Developmental Biology Centre, led by the head of the Functional Genomics Unit - Laboratory 3, David Gubb from the U.K., has found the regulating mechanism of the serum protein Serpin (SERin Protease INhibitor) thanks to the fruit fly, Drosophila melanogaster. The research project has been published in the prestigious scientific journal PLoS Genetics.
Serpins are a numerous group of proteins with similar structures, capable of inhibiting proteolytic enzymes (proteases). Since serpins control cellular processes, such as resistance to infection by fungi and bacteria, the coagulation of blood and inflammation, scientific researchers are keen to find out more about them.
As David Gubb says: "in humans fungal infections are very important, especially in cases where the immune system is depressed - for instance, in cases of HIV/AIDS, medication following an organ transplant, and fungi such as Aspergillus, very common in humans. In such cases, they can lead to death within 24 hours. Many people with AIDS die of fungal infections."
Serpins have been studied extensively in mammals, where they regulate multiple extra-cellular proteolytic cascades. Coagulation, inflammation and complement pathways are controlled by various serpins (α1-Antithrombin, α1-Antitrypsin and C1 Inhibitor, respectively), whilst Plasminogen Activator Inhibitor type-1 modulates angiogenesis, affecting the healing of wounds and tumour growth.
Disturbed serpin metabolism underlies a great number of human genetic diseases, known as serpinopathies, associated with a failure to clear serpin polymers and mutated proteins that produce Necrotic molecules similar to inactive polymers.
Up to now nothing has been known about the mechanism which degrades the proteins that circulate in the fly's blood serum. This process is important when the insects are living normally and becomes critical when toxic proteins build up. In the case of humans, many of the proteins that circulate in the bloodstream are synthesized in the liver. The liver also re-absorbs and degrades proteins that have been denatured. In flies, many proteins are produced in the fat-body, which is the organ that carries out many of the functions of the human liver. The research project, however, demonstrates that the process of 'clearing' denatured proteins is carried out not in the fly's fat-body, but in giant cells called 'garland cells'.
The research team's particular purpose is to understand how the innate immune reaction of the fruit fly (Drosophila melanogaster) is regulated in bacterial and fungal infections. In recent years the fruit fly has served as a very high-yielding model for understanding the human immune reaction. For instance, in humans, Toll-like receptors (a family of type I transmembrane proteins that form part of the innate immune system), which are very sensitive to bacterial and viral infections, were discovered because of their likeness to the Toll gene (a gene involved in the fruit fly's innate immune response).
Humans react to infections by means of antibodies that attack the invading pathogens. These antibodies provide long-lasting protection against individual pathogens. The antibody response, however, is slow and may take weeks to develop, which it does only following an innate reaction caused by a recent infection.
In contrast to this 'acquired' response, humans undergo an innate reaction caused by anti-microbial peptides and the activation of phagocytic cells. Were it not for this innate reaction, infections could claim the lives of humans before our bodies were able to generate new antibodies. The fruit fly doesn't possess any equivalent to the antibody system, but its innate immune reaction is very similar to humans'.
In nec (Necrotic serpin) null mutants, the Toll-mediated immune response is constitutively activated, even in the absence of infection, implying that Nec (the Necrotic protein) continually restrains this immune response.