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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,8,25]]},"abstract":"<jats:p>Hsp70 chaperones are central regulators of proteostasis, mediating folding, refolding, degradation, and aggregation-prevention. Their activity is tuned by the diverse J-domain proteins (JDPs), which both recruit client proteins and stimulate Hsp70 ATP hydrolysis via interaction with a conserved J-domain. The cytosol contains four Hsp70 paralogs\u2014the stress-inducible HSPA1A\/B and HSPA6, and the constitutively expressed HSPA8. Whether these act redundantly or carry distinct cellular functions has remained unresolved. Here, we systematically map the interactions of cytosolic Hsp70s with broad-specificity JDPs to elucidate how paralog identity shapes cellular function. We found that despite the high conservation of the JDP\u2013Hsp70 interaction sites, the affinities of these interactions and their functionality varied greatly. HSPA8 behaves as a generalist, engaging all JDP classes with comparable affinity, consistent with its housekeeping role. By contrast, HSPA1 preferentially binds canonical Class A and B JDPs, while showing only weak binding to Class B\u2032. Therefore, under stress, HSPA1 pairs only with Class A\/B JDPs to support robust protein refolding, while freeing Class B\u2032 to suppress protein aggregation in an Hsp70-independent manner. Most unexpectedly, HSPA6, the most stress-inducible paralog, binds selectivity to Class B JDPs, losing interactions with both Class A and B\u2032. Thus, under severe stress, HSPA6 works exclusively with Class B JDPs to ensure ATP-dependent protein repair, while freeing Class A and B\u2032 JDPs to act independently of Hsp70 to protect damaged\/misfolded proteins. Our findings reveal an evolved hierarchy of paralog-specific JDP couplings that dynamically rewires the Hsp70 network from active repair to protection during stress.<\/jats:p>","DOI":"10.1073\/pnas.2534903123","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T17:59:27Z","timestamp":1787075967000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["Human Hsp70 paralogs display selective J-domain interactions tuning proteostasis under stress"],"prefix":"10.1073","volume":"123","author":[{"given":"Roni","family":"Suhler","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0316ej306","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Chemical and Structural Biology, Weizmann Institute of Science","place":["Rehovot, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7713-4857","authenticated-orcid":false,"given":"Lars J. 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