A life expectancy ‘molecular switch’ could hold the key to living longer

CHIP can control life-prolonging signals like insulin receptors in the cell better alone than in pairs.
Nergis Firtina
CHIP.jpg
C.elegans wild-type CHIP (left); C.elegans monomeric CHIP (right)

University of Cologne  

A single protein can more effectively modulate aging signals compared to a group, according to researchers from the University of Cologne.

In a recent study, researchers have discovered the protein CHIP can control life-prolonging signals - like insulin receptors - in the cell better alone than in pairs.

The results were published in the journal Molecular Cell on August 25.

What is the real story?

In cellular stress situations, CHIP is most often seen as a homodimer, a connection of two identical proteins. Its main function is to destroy damaged and improperly folded proteins. CHIP purifies the cell in this way, as per the statement.

To accomplish this, CHIP works with helper proteins to bind misfolded proteins with chains of the tiny protein ubiquitin.

The cell, as a result, recognizes and eliminates damaged proteins. Furthermore, CHIP regulates the transmission of the insulin receptor's signal. Life-extending gene products cannot be activated because CHIP attaches to the receptor and breaks it down.

Life-extending gene products cannot be activated because CHIP attaches to the receptor and breaks it down.

A life expectancy ‘molecular switch’ could hold the key to living longer
The CHIP monomer regulates insulin receptor turnover and longevity

The research team led by Prof. Dr. Thorsten Hoppe has now demonstrated that CHIP may also identify itself with ubiquitin, preventing the formation of its dimer. They also used human cells and the nematode Caenorhabditis elegans in the test.

“Whether CHIP works alone or as a pair depends on the state of the cell. Under stress, there are too many misfolded proteins as well as the helper proteins that bind to CHIP and prevent auto-ubiquitylation, the self-labeling with ubiquitin,’ said Vishnu Balaji, first author of the study.

"After CHIP successfully cleans up the defective proteins, it can also mark the helper proteins for degradation. This allows CHIP to ubiquitylate itself and function as a monomer again,’ he explained," he also explained.

“It’s interesting that the monomer-dimer balance of CHIP seems to be disrupted in neurodegenerative diseases,’ said Thorsten Hoppe.

What's next?

The next step is for the researchers to determine if there are any further proteins or receptors that the CHIP monomer interacts with and controls their function. In order to create more specialized treatments in the future, researchers are particularly curious about which tissues, organs, and diseases have higher concentrations of CHIP monomers or dimers.

Study abstract

The high substrate selectivity of the ubiquitin/proteasome system is mediated by a large group of E3 ubiquitin ligases. The ubiquitin ligase CHIP regulates the degradation of chaperone-controlled and chaperone-independent proteins. To understand how CHIP mediates substrate selection and processing, we performed a structure-function analysis of CHIP and addressed its physiological role in Caenorhabditis elegans and human cells. The conserved function of CHIP in chaperone-assisted degradation requires dimer formation to mediate proteotoxic stress resistance and to prevent protein aggregation. The CHIP monomer, however, promotes the turnover of the membrane-bound insulin receptor and longevity. The dimer-monomer transition is regulated by CHIP autoubiquitylation and chaperone binding, which provides a feedback loop that controls CHIP activity in response to cellular stress. Because CHIP also binds other E3 ligases, such as Parkin, the molecular switch mechanism described here could be a general concept for the regulation of substrate selectivity and ubiquitylation by combining different E3s.

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