Friday, February 3, 2023

Signal transmission in the immune and nervous system using NEMO

Jörg Tatzelt, Konstanze Winklhofer and Simran Goel (from left) carried out the investigations together.
 Photo Credit: RUB, Marquard

Certain biomolecules in the form of active complexes temporarily accumulate in cells. This can be crucial for their functionality.

When transmitting signals within cells, many individual steps interlock. Among other things, proteins are provided with certain building blocks that switch their function on or off. In order to ensure fast signal transmission, these building blocks accumulate in the cell at certain locations for a limited time; Researchers speak of biomolecular condensates. A team around Prof. Dr. Konstanze Winklhofer, head of the Molecular Cell Biology Chair at the Ruhr University Bochum, has shown that the NEMO protein also forms condensates and which mechanism underlies NEMO condensate formation. The findings are important for understanding signal transmissions in the immune and nervous systems. The researchers report in the Life Science Alliance journal.

Switch proteins on and off

Various cellular processes are initiated by binding messenger substances such as hormones, neurotransmitters or cytokines to specific receptors in the cell membrane. "The signal transmission must be strictly regulated in terms of time and space in order to trigger an adequate cellular reaction on the one hand and to avoid excessive reactions on the other," explains Konstanze Winklhofer. The regulation takes place, for example, by temporarily changing proteins, for example by attaching phosphate groups or chains consisting of small ubiquitin proteins.

In order to enable quick regulation, the required biomolecules can come together in so-called condensates. "You can imagine that these molecules temporarily accumulate in certain places in the cell," explains Konstanze Winklhofer. This accumulation of molecules is like a drop, but has no external delimitation by a membrane.

NEMO needs ubiquitin chains

Konstanze Winklhofer's working group was now able to show that such biomolecular condensates are formed when the transcription factor NF-κB is activated. This transcription factor is activated by various signaling pathways, for example in immune reactions by the cytokines interleukin-1 (IL-1) and tumor necrosis factor (TNF) or by various factors in the nervous system.

The protein NEMO (NF-κB essential modulator) plays a central role in the activation of NF-κB. Various NF-κB-activating stimuli cause chains from ubiquitin molecules to form. NEMO binds to these chains, changes its conformation and thereby activates certain enzymes that are necessary for signal transmission.

Konstanze Winklhofer and her team found that NEMO can only form biomolecular condensates if it interacts with ubiquitin chains. If the binding of NEMO to ubiquitin chains is impaired by a mutation in the NEMO gene, no condensates form and NF-κB is not activated.

Mutation prevents NEMO from functioning

"We identified a mutation in the NEMO gene on the X chromosome that causes NEMO to no longer bind to the ubiquitin chains," reports Konstanze Winklhofer. This makes NEMO inoperable. The mutant is associated with the clinical picture Incontinentia pigmenti. Clinical manifestations of this disease are abnormalities in the skin and changes in the central nervous system. The disease is usually fatal to male sufferers because they only have an X chromosome. "The characterization of this NEMO mutant in cellular models made a significant contribution to the understanding of signal processes in the context of NF-κB activation," says Konstanze Winklhofer. "In further studies, we are currently investigating the role of NEMO in specific functions of nerve cells and immune cells".

Published in journalLife Science Alliance

Source/CreditRuhr University Bochum

Reference Number: bio020323_01

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