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Comprehensive interactome profiling of the human Hsp70 network highlights functional differentiation of J domains
First Author: Benjamin Piette
  Hsp70s comprise a deeply conserved chaperone family that has a central role in maintaining protein homeostasis. In humans, Hsp70 function and client specificity are tightly regulated by 49 different co-factors known as J domain proteins (JDPs), whose cellular function and client specificity have, however, largely remained elusive. We have combined affinity purification-mass spectrometry (AP-MS) and proximity-dependent biotinylation (BioID) to characterize the interaction network of all human JDPs and Hsp70 family members, revealing over 1,200 physical interactions and nearly 3,500 proximity interactions. The resulting network suggests specific functions for many uncharacterized JDPs, and we establish the role of conserved but poorly studied JDPs DNAJC9 and DNAJC27 in histone chaperoning and ciliogenesis, respectively. Unexpectedly, we find that the J domain of DNAJC27 but not of other JDPs can fully replace the function of endogenous DNAJC27, suggesting a previously unappreciated role for J domains themselves in JDP specificity. More broadly, our work expands the role of the Hsp70-regulated proteostasis network in human cells and provides a platform for further discovery of JDP-dependent cellular functions.