Human Hsp70 paralogs display selective J-domain interactions tuning proteostasis under stress
TL;DR
An evolved hierarchy of paralog-specific JDP couplings that dynamically rewires the Hsp70 network from active repair to protection during stress is revealed, revealing an evolved hierarchy of paralog-specific JDP couplings that dynamically rewires the Hsp70 network from active repair to protection during stress.
Abstract
Significance Proteostasis depends on the coordinated actions of Hsp70 chaperones and their diverse J-domain protein (JDP) cochaperones, yet whether these act redundantly or carry distinct cellular functions has remained unresolved. Here, we uncover that despite being highly conserved, the J-domain exhibits subtle sequence-level differences across different JDP classes, which tune the affinity and specificity of JDPs for Hsp70 paralogs. As cellular stress increases, stress-inducible Hsp70s interact with an increasingly selective subset of JDPs, effectively releasing other broad-specificity JDPs to function as stand-alone chaperones, independently of Hsp70, protecting cellular clients from misfolding and aggregation. Together, these results reveal an evolved hierarchy of paralog-specific JDP couplings that dynamically rewires the Hsp70 network during stress from adenosine triphosphate-dependent repair to protective containment, ensuring robust proteostasis.
