Another publication on the key protein quality control ubiquitin ligase CHIP. CHIP regulates the degradation of chaperone-dependent and chaperone-independent proteins. Our studies have better understood how CHIP mediates substrate selection and processing. We revealed that CHIP exists as a dimer and a monomer with different substrate-specific functions. The CHIP dimer mediates the degradation of damaged proteins. The CHIP monomer regulates insulin receptor turnover and longevity. Dimer-monomer switching is controlled by CHIP auto-ubiquitylation and chaperone binding. In summary, we identified a conserved molecular switch mechanism that controls substrate specificity of CHIP and that may be related to the pathophysiology of age-related diseases.

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