Mechanisms and regulation of the Hsp70 chaperone network

Oct 28, 2025Nature reviews. Molecular cell biology

How the Hsp70 protein system works and is controlled

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Abstract

The 50 human J-domain proteins (JDPs) provide Hsp70 chaperones with remarkable client specificity, comparable to nearly 600 E3 ubiquitin ligases.

Hsp70 chaperones are crucial for maintaining protein homeostasis by assisting in the proper folding and quality control of proteins.
JDPs either recruit Hsp70s to specific cellular locations or directly bind to substrate proteins through various binding sites.
The interaction between JDPs and Hsp70s influences whether client proteins are properly folded or targeted for degradation.
Recent findings reveal that the Hsp70 network exhibits significant versatility and complexity in regulating protein fate.
Insights into Hsp70 regulation may lead to more targeted approaches for treating ageing-related and protein folding diseases.

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The 70-kDa heat shock protein (Hsp70) chaperone is essential to maintain cellular protein homeostasis, facilitating the folding, assembly, membrane translocation and quality control of proteins. Hsp70s achieve their functions through 'selective promiscuity', interacting with a wide range of substrate proteins while minimizing undesired interactions. J-domain proteins (JDPs) and nucleotide exchange factors (NEFs) are key to substrate recognition, remodelling and release from chaperone complexes. JDPs either target Hsp70s to specific subcellular sites where substrates reside (recruiters) or bind substrates directly by using highly specific (specialists) or multiple, versatile (generalists) binding sites. Through diverse substrate-binding modes and regulatory mechanisms, the 50 human JDPs confer remarkable client specificity to Hsp70s, a function that is comparable to that achieved by close to 600 E3 ubiquitin ligases in targeting proteins for degradation. Moreover, JDPs, together with NEFs, dictate the fate of Hsp70 clients by directing them to distinct protein quality control pathways, resulting in their folding or degradation. These recent mechanistic insights into Hsp70 regulation not only highlight the versatility and complexity of the Hsp70 network but also offer new avenues for more specific interventions in ageing-related and other protein folding diseases.

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Mechanisms and regulation of the Hsp70 chaperone network

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