A new study shows that the protein CHIP can inhibit the insulin receptor much more efficiently alone than as a composite, which is its common form. In cellular stress situations, CHIP is usually responsible as a dimer – a composite of two coupled proteins – primarily for the degradation of misfolded proteins. CHIP thus cleans up the cell. To do this, CHIP tags proteins with a chain of small proteins called ubiquitin. Together with helper proteins, defective proteins are thus recognized and eradicated by the cell. Another function is the regulation of insulin receptor signalling. CHIP binds the receptor, thus acting as a brake, and stops signal transmission. That way, certain genes cannot be activated, which prolongs the life span.
A Cologne-based research team has now shown in experiments with the nematode Caenorhabditis elegans and human cells that CHIP can label itself with ubiquitin, which prevents dimer formation. CHIP remains alone as a so-called monomer and can perform its function as a brake on the insulin signalling pathway better in this formation than in the dimer compound. The study conducted by scientists in the team of Professor Dr Thorsten Hoppe at the University of Cologne’s CECAD Cluster of Excellence for Aging Research was published under the title ‘A Dimer-Monomer Switch Controls CHIP-Dependent Substrate Ubiquitylation and Processing’ in Molecular Cell.
‘Whether CHIP works alone or as a team is determined by the status of the cell. If there are too many misfolded proteins and also too many helper proteins, auto ubiquitination, the self-labelling with ubiquitin, is prevented. CHIP first has to put things in order,’ said Vishnu Balaji, first author of the study. ‘After successfully cleaning up the faulty proteins, CHIP can also tag the helper proteins and make them degrade,’ he explained. Thus, for the body to function smoothly, there must be a balance between the monomeric and dimeric states of CHIP. ‘It is interesting that the monomer-dimer balance of CHIP seems to be disturbed in diseases,’ said Thorsten Hoppe. ‘For example, in spinocerebellar ataxias, a neurodegenerative disease, different sites of the protein are mutated and CHIP works preferentially as a dimer. Here, a shift to more monomers would be a possible therapeutic approach.’ In the next step, the scientists want to find out whether there are more proteins or receptors to which the CHIP monomer binds, and thus regulates their function. The researchers are also interested in finding out in which tissues and organs and in which diseases CHIP monomers or dimers are increasingly present in order to be able to develop more targeted therapies in the future.
Media Contact:
Professor Dr Thorsten Hoppe
+49 221 478 84218
thorsten.hoppe@uni-koeln.de
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Dr Anna Euteneuer
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Publication:
Balaji V, Müller L, Lorenz R, Kevei E, Zhang WH, Santiago U, Gebauer J, Llamas E, Vilchez D, Camacho CJ, Pokrzywa W, Hoppe T. A Dimer-Monomer Switch Controls CHIP-Dependent Substrate Ubiquitylation and
Processing. Mol Cell. 2022
https://www.cell.com/molecular-cell/fulltext/S1097-2765(22)00756-0