Promising CHIP Protein Could Act as ‘Molecular Switch’ to Longevity

Researchers from the University of Cologne reported that a single protein could modulate aging signals more effectively compared to a group of proteins. According to their recent publication, the team has discovered the protein CHIP (carboxy-terminus of Hsc70-interacting protein) can control life-prolonging signals such as insulin receptors in the cell more efficiently alone than in a paired state. The journal Molecular Cell published the results on August 25. 

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Monomer-Dimer Conversion of CHIP

Under cellular stress situations, protein CHIP usually appears as a homodimer, an association of two identical proteins, and primarily serves to degrade misfolded or defective proteins to clean up the cell. It will collaborate with helper proteins to attach a chain of the small, regulatory protein, ubiquitin, to misfolded or defective proteins. The labeled proteins are then recognized and eliminated. Moreover, CHIP also regulates the signal transduction of the insulin receptor by binding ubiquitin to the receptor to degrade it and stop the activation of life-extending gene products.

In the recent study led by Professor Dr. Thorsten Hoppe, the team used nematode Caenorhabditis elegans and human cells as models. It successfully showed that CHIP not only labels others but also labels itself with ubiquitin to prevent its dimer formation. Surprisingly, the CHIP monomer is more efficient than the CHIP dimer in regulating insulin signaling.

However, scientists found that whether CHIP works alone or as a pair depends on the state of the cell. For instance, under stress conditions, too many misfolded proteins and helper proteins bind to CHIP and prevent auto-ubiquitylation (the self-labeling of CHIP with ubiquitin). After CHIP successfully cleans up the defective proteins, it can also mark the helper proteins for degradation, allowing CHIP to ubiquitylate itself and function as a monomer again. To ensure the process functions smoothly, the scientists hypothesized there must be a balance between the monomeric and dimeric states of CHIP. 

Setting the Stage for a New Class of Targeted Therapies

The disrupted monomer-dimer balance of CHIP in neurodegenerative diseases grabs the attention of scientists. For instance, in the case of Alzheimer’s Disease, the most common neurodegenerative disease worldwide, its pathology is closely related to beta-amyloid (Aβ) deposits and hyperphosphorylated tau(p-tau). Several studies have reported that CHIP can directly ubiquitinate and eliminate p-tau, while in vivo studies also showed that overexpressing CHIP could reduce tau phosphorylation. 

To sum up, the expression level of CHIP is extremely important to develop novel targeted therapy. The next step for scientists is to determine whether there are any further proteins or receptors that the CHIP monomer interacts with and regulates their function subsequently. The concentrations of CHIP monomers or dimers in different tissues, organs, and diseases are also left to be identified.

Author

Nai Ye Yeat