A critical role for CHIP in the aggresome pathway

Area of Science:

• Cellular Biology
• Protein Degradation Pathways
• Stress Responses

Background:

• Aggresome formation is increasingly recognized as a physiological stress response, not solely for misfolded proteins.
• Inducible nitric oxide synthase (iNOS) exemplifies this by forming physiologic aggresomes.
• The carboxy terminus of Hsp70-interacting protein (CHIP) is a known mediator of protein ubiquitination and proteasomal degradation.

Purpose of the Study:

• To investigate the role of CHIP in the aggresome pathway.
• To elucidate CHIP's function in the formation and regulation of physiologic aggresomes.
• To determine CHIP's involvement in targeting specific proteins to aggresomes.

Main Methods:

• Investigated CHIP's interaction with inducible nitric oxide synthase (iNOS).
• Assessed CHIP's role in iNOS ubiquitination, proteasomal degradation, and aggresomal sequestration.
• Examined CHIP's requirement for aggresome formation using mutant cystic fibrosis transconductance regulator (CFTRDeltaF508).

Main Results:

• CHIP interacts with iNOS, promoting its ubiquitination and degradation via the proteasome, followed by aggresomal sequestration.
• CHIP is essential for the maturation of iNOS preaggresome structures into aggresomes.
• CHIP's ubiquitin ligase activity is critical for targeting proteins to aggresomes, facilitating interaction with histone deacetylase 6 and the dynein motor.

Conclusions:

• CHIP plays a critical and previously unrecognized role in the aggresome pathway.
• CHIP regulates both protein degradation and sequestration to aggresomes.
• CHIP is a key component in the cellular response to protein stress and misfolding, impacting pathways involving iNOS and CFTRDeltaF508.