Scientists discover a molecular switch that controls life expectancy

A single protein can control aging signals more effectively than a group.

According to recent research, CHIP can control insulin receptors more effectively while acting alone than if in pairs. In cases of cellular stress, CHIP often appears as a homodimer–a conjugation of two identical proteins–and primarily serves to destroy defective and defective proteins. Thus CHIP cleans the cell. In order to do this, CHIP works with the helper proteins to link a chain of the small protein ubiquitin to the denatured proteins.

As a result, the cell detects and eliminates defective proteins. Moreover, CHIP controls insulin receptor signal transduction. CHIP binds to and degrades receptors, preventing the activation of life-prolonging gene products.

researchers from University of Cologne It has now been shown by tests using human cells and the nematode Caenorhabditis elegans that CHIP can also label itself ubiquitin, preventing the formation of its dimers. CHIP monomer regulates insulin signaling more effectively than dimers. The research was carried out by the University of Cologne’s Excellence Group for Cellular Stress Responses in Aging-related Diseases (CECAD) and was recently published in the journal. molecular cell.

Whether CHIP functions alone or as a pair depends on the state of the cell. Under stress, there are too many denatured proteins as well as helper proteins that bind to CHIP and prevent its ubiquitylation, which is self-labeling with ubiquitin,” said Vishnu Balaji, first author of the study. “After CHIP successfully cleans out the defective proteins, it can also Identification of hydrolyzed proteins. This allows CHIP to be ubiquitous and act as a monomer again,” he explained.

Thus, for the body to function smoothly, there must be a balance between the unilateral and dual states of CHIP. “Interestingly, the monomer-dimer balance of CHIP appears to be disrupted in neurodegenerative diseases,” Thorsten Hoppe said. In spinocerebellar ataxias, for example, different sites of CHIP are mutated, and they mostly function as a diploid. Here, switching to more monomers would be a potential therapeutic approach.”

In the next step, the scientists want to know if there are other proteins or receptors to which the CHIP monomer binds, and thus regulates its function. Researchers are also interested in knowing which tissues, organs and diseases in which CHIP monomers or dimers occur in greater numbers, in order to be able to develop more targeted therapies in the future.

Reference: “A bi-monomer switch that controls chip-dependent substrate diffusion and processing” by Vishnu Balaji, Leonie Muller, Robin Lorenz, Eva Keefe, William H. Camacho, Wojciech Bokrizo and Thorsten Hobe, August 25, 2022, Available here. molecular cell.
DOI: 10.1016 / j.molcel.2022.08.003