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New gateway for cellular uptake of nutrients

An international team led by researchers at Helmholtz Zentrum München has discovered a mechanism that could help develop new strategies for the treatment of metabolic diseases. The mechanism regulates the number of nutrient transporters on the cell surface. The work has now been published in Nature Communications.

GLUT1 (red) in lysosomes (yellow) after SNX27 loss in U2OS cells (nucleus: blue). © Dr. Aurelia Stangl, Department of Cellular Signal Integration, Helmholtz Zentrum München.

Nutrient transporters are critical for the cellular uptake of nutrients such as glucose and amino acids. Dysregulations in the quantity of these transporters on the cell surface can be linked to metabolic diseases. The trafficking of nutrient transporters to the cell surface is controlled by a protein complex known as 'Sorting Nexin 27' (SNX27) retromer. Defects in this complex lead to reduced nutrient uptake, metabolism and weight gain. So far, it was not known what cellular factors precisely control the shuttling of nutrient transporters by the SNX27 retromer.

Unexpected mechanism revealed

A team of researchers led by Prof. Daniel Krappmann at Helmholtz Zentrum München succeeded in identifying the OTULIN protein as a factor that strongly influences the mode of operation and hence the effectiveness of the SNX27 retromer. Previous work involving the Krappmann group has already helped to describe an important enzymatic function of OTULIN in the regulation of cellular signaling processes (see Keusekotten et al., Cell 2013).

Now, the team has discovered an unexpected mechanism that controls the amount of nutrient transporters on the cell surface. The researchers were able to define a moonlight function, i.e. a second non-enzymatic role of OTULIN in regulating the SNX27 retromer. Within the cells, OTULIN binds tightly to SNX27 and thus prevents the formation of the SNX27 retromer complex. The findings also shows that the binding of OTULIN to SNX27 significantly reduces the surface expression of important transport proteins such as the glucose transporter GLUT1 and the amino acid transporter SLC1A4.

This new knowledge influences our understanding of how the absorption of nutrients in human cells can be controlled by the accessibility of nutrient transporters. The team is currently working on clarifying the dynamics of the regulation of the retromer through OTULIN. The aim is to evaluate if manipulation of this regulation may be a future therapeutic strategy to control cellular nutrient uptake and thus metabolic processes.

A prime example of international research

This research is result of a close international cooperation between Helmholtz Zentrum München and scientists at the Medical Research Council (MRC) in Cambridge (UK), the University of Oxford (UK), UbiQ in Amsterdam (Netherlands) and the Walter and Eliza Hall Institute (WEHI) in Melbourne (Australia).

“The success of this study is largely based on the excellent cooperation between scientists from very different disciplines," explains Krappmann. "The unexpected control mechanism could only be revealed through the close interplay of chemical biology, mass spectrometry, biophysics and structural biology with molecular and cell biological techniques.”

Further information

Original publication:
Stangl et al. (2019): Regulation of the endosomal SNX27-retromer by OTULIN. Nat. Commun, DOI: 10.1038/s41467-019-12309-z

As German Research Center for Environmental Health, Helmholtz Zentrum München pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes mellitus, allergies and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München has about 2,500 staff members and is headquartered in Neuherberg in the north of Munich. Helmholtz Zentrum München is a member of the Helmholtz Association, a community of 19 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. 

Die Abteilung Zelluläre Signalintegration (AZS) ist dem Institut für molekulare Toxikologie und Pharmakologie (TOXI) angeschlossen und forscht für ein besseres Verständnis von Signalnetzwerken. Dabei stehen das Zusammenspiel von Proteinen in Komplexen und die Auswirkungen posttranslationaler Modifikationen im Mittelpunkt. Ziel ist es, die Fehlregulation der Signalkomplexe im Immunsystem bei Entzündungserkrankungen und der Entwicklung von Lymphomen zu verstehen und pharmakologisch anzugreifen.

The Institute of Diabetes and Obesity (IDO) studies the diseases of the metabolic syndrome by means of systems biological and translational approaches on the basis of cellular systems, genetically modified mouse models and clinical intervention studies. It seeks to discover new signaling pathways in order to develop innovative therapeutic approaches for the personalized prevention and treatment of obesity, diabetes and their concomitant diseases. IDO is part of the Helmholtz Diabetes Center (HDC).