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In a nutshell:
• Important for infection: Researchers have shown that parasites of the genus Leishmania require the protein TKUL to maintain infections of host cells.
• Two enzymes in one molecule: TKUL has two infection-relevant enzyme functions: a kinase and a ubiquitin ligase.
• Unusual mechanism: The kinase acts as a molecular switch that activates the ubiquitin ligase. This occurs through structural rearrangements.
• New molecular target: Kinase inhibitors can block both enzymatic activities of TKUL, thus providing new therapeutic opportunities for leishmaniasis.
Leishmaniasis belongs to the class of neglected tropical diseases (NTDs) that particularly affect people in the poorest tropical regions of the world. NTDs are less studied and therapeutically addressed than other diseases. Leishmaniasis is caused by parasites of the genus Leishmania, which are transmitted to humans through the bite of infected sand flies. However, leishmaniasis is now also spreading increasingly in temperate zones of Europe and North America, owing to progressive climate change, ongoing armed conflicts with forced migration, and rising international travel.
The World Health Organization estimates that up to one million people worldwide contract the cutaneous form of leishmaniasis, causing skin lesions, per year. Additionally, 50,000 to 90,000 new cases of the severe visceral disease form emerge annually. Visceral leishmaniasis, also known as kala-azar or black fever, primarily affects internal organs such as the liver and spleen. If untreated, visceral leishmaniasis is life-threatening, leading to death in over 95 percent of cases.
New therapies required
Currently, there is no way to prevent leishmaniasis, as no vaccines or preventive drugs exist. To treat patients, only a few medications are available, including miltefosine. However, most of these substances do not specifically target Leishmania, cause severe side effects, and increasingly lose efficacy due to the parasite resistances. Furthermore, the drugs are often too expensive or unavailable in the most affected regions, or they require injections by trained medical personnel. The development of new, tailored therapies against leishmaniasis is therefore an important global challenge. A crucial step in this process is to identify parasite-specific molecular targets.
Crucial for infection
A research team led by Sonja Lorenz at the Max Planck Institute (MPI) for Multidisciplinary Sciences in Göttingen (Germany) has characterized a previously unexplored, parasite-specific protein, TKUL, from the pathogen Leishmania mexicana and discovered that it plays key roles during infections. The associated parasitological studies were carried out by the research groups of Christian Janzen at the University of Würzburg and Ulrike Schleicher at the University Hospital of Erlangen. The lack of TKUL in the human and animal host organisms of Leishmania, along with its unique structure, offer new perspectives in targeted therapies against leishmaniasis.
One protein, two enzyme activities
TKUL combines two enzyme components that typically only occur in separate proteins: One part of the protein is a kinase domain, which usually controls cellular signaling pathways by transferring phosphate groups. The second component is a ubiquitin ligase domain that tags proteins with the small protein modifier ubiquitin. This modification often serves to break down excess or defective proteins and reuse their building blocks – a process that is essential for keeping cells healthy.
New tools against leishmaniasis
Lorenz’s research team has discovered that the two enzymatic activities of TKUL are coupled to each other. “The kinase acts as a molecular ‘switch’ that activates the ubiquitin ligase. However, this does not occur – as expected – through the transfer of a phosphate group to the ubiquitin ligase domain, but via effective structural rearrangements,” explains Thornton Fokkens, a postdoctoral scientist in the research group at the MPI who generated the mechanistic findings as part of his PhD thesis. “Due to this unique activation mechanism, we can block the ubiquitin ligase activity of TKUL with inhibitors that bind to the kinase domain,” he adds. Lorenz sees this as a major advantage: “Finding inhibitors for ubiquitin ligases is very difficult. Here, we can use a kinase inhibitor to switch off the ubiquitin ligase function of TKUL in a convenient, indirect way.”
The next goal of her research group is to further develop these inhibitors to specifically block TKUL activity in infection models. “The substances will be valuable tools for elucidating the precise role of TKUL in Leishmania infections, possibly opening new therapeutic opportunities,” the group leader says.
Dr. Sonja Lorenz
Reserach Group Ubiquitin Signaling Specificity
Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
Phone: +49 551 201-1757
Email: sonja.lorenz@mpinat.mpg.de
Fokkens, T. J.; Rauh, E. T.; Wolter, M.; Sebald, H.; Mitnacht, M.; Ainatzi, S.; Sprick, S.; Teschke, L.; Eisenhuth, N.; Huibregtse, J. M. et al.: A Leishmania virulence factor harnesses an allosteric kinase switch to regulate its ubiquitin ligase activity. Molecular Cell (2025).
https://doi.org/10.1016/j.molcel.2025.09.002
https://www.mpinat.mpg.de/5143184/pr_2520 – Original press release
https://www.mpinat.mpg.de/lorenz – Research Group Ubiquitin Signaling Specificity, Max Planck Institute for Multidisciplinary Sciences
Leishmania parasites can only maintain infections with the help of the protein TKUL, which contains ...
Source: Johannes Pauly, Sonja Lorenz
Copyright: Max Planck Institute for Multidisciplinary Sciences
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Leishmania parasites can only maintain infections with the help of the protein TKUL, which contains ...
Source: Johannes Pauly, Sonja Lorenz
Copyright: Max Planck Institute for Multidisciplinary Sciences
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