Chaperone isoform and interactome mapping reveals functional diversification of DNAJA2-DNAJA4 complexes via stress-regulated isoforms

The human HSP70 chaperone network maintains cellular proteostasis through a diverse repertoire of HSP70s and co-chaperones. Researchers have now mapped the isoform, tissue-expression, and interaction landscapes of this network, revealing a modular interactome containing both known and novel DNAJ-DNAJ interactions. They found that there are differences in the expression of isoforms between different tissues, as well as widespread co-expression of alternative isoforms, suggesting additional ways in which these proteins can diversify their functions.

Focusing on an uncharacterized complex involving DNAJA2 and DNAJA4, researchers identified a stress-inducible isoform of DNAJA4 called DNAJA4-CTD-II. This isoform was found to interact with both DNAJA2 and DNAJA4, and this interaction was enhanced following exposure to sodium arsenite, a stress-inducing agent. Functionally, DNAJA4-CTD-II was found to localize with aggregates of the protein TDP-43, and it significantly suppressed the accumulation of these aggregates in a DNAJA2-dependent manner.

Overall, this research reveals extensive and previously unknown complexity within the HSP70 network, including isoform-dependent hetero-complex remodeling as a new layer of regulation for chaperone networks.