Chaperone isoform and interactome mapping reveals functional diversification of DNAJA2-DNAJA4 complexes via stress-regulated isoforms
- 1Technion - Israel Institute of Technology
Abstract
The human HSP70 chaperone network maintains cellular proteostasis through a diverse repertoire of HSP70s and co-chaperones. Here we examine alternative isoforms and co-chaperone hetero-complexes as additional sources of network complexity. To that end, we systematically mapped the isoform, tissue-expression, and interaction landscapes of the human HSP70 network, revealing a modular interactome containing known and novel DNAJ-DNAJ interactions. We found both tissue-expression isoform divergence as well as widespread alternative-canonical isoform co-expression, suggesting additional modes of functional diversification. Focusing on the uncharacterized DNAJA2-DNAJA4 hetero-complex, we identified the stress-inducible isoform DNAJA4-CTD-II. DNAJA4-CTD-II formed hetero-complexes with DNAJA2 and DNAJA4, with both interactions enhanced following sodium arsenite stress. Functionally, DNAJA4-CTD-II co-localized with TDP-43 aggregates and significantly suppressed their accumulation in a DNAJA2-dependent manner. Together, our data reveal extensive, uncharted isoform and interaction complexity within the HSP70 network, and uncover isoform-dependent hetero-complex remodeling as a new layer of chaperone network regulation.
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BibTeX
@misc{kadah2026chaperone,
title = {{Chaperone isoform and interactome mapping reveals functional diversification of DNAJA2-DNAJA4 complexes via stress-regulated isoforms}},
author = {T. Kadah and N. Akaree and A. Brodov-Nevo and A. Meller and F. Levy-Adam and R. Shalgi},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.23.753896},
url = {https://www.biorxiv.org/content/10.64898/2026.09.23.753896v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Chaperone isoform and interactome mapping reveals functional diversification of DNAJA2-DNAJA4 complexes via stress-regulated isoforms
AU - T. Kadah
AU - N. Akaree
AU - A. Brodov-Nevo
AU - A. Meller
AU - F. Levy-Adam
AU - R. Shalgi
PY - 2026
DA - 2026/09/23
PB - bioRxiv
DO - 10.64898/2026.09.23.753896
UR - https://www.biorxiv.org/content/10.64898/2026.09.23.753896v1
AB - The human HSP70 chaperone network maintains cellular proteostasis through a diverse repertoire of HSP70s and co-chaperones. Here we examine alternative isoforms and co-chaperone hetero-complexes as additional sources of network complexity. To that end, we systematically mapped the isoform, tissue-expression, and interaction landscapes of the human HSP70 network, revealing a modular interactome containing known and novel DNAJ-DNAJ interactions. We found both tissue-expression isoform divergence as well as widespread alternative-canonical isoform co-expression, suggesting additional modes of functional diversification. Focusing on the uncharacterized DNAJA2-DNAJA4 hetero-complex, we identified the stress-inducible isoform DNAJA4-CTD-II. DNAJA4-CTD-II formed hetero-complexes with DNAJA2 and DNAJA4, with both interactions enhanced following sodium arsenite stress. Functionally, DNAJA4-CTD-II co-localized with TDP-43 aggregates and significantly suppressed their accumulation in a DNAJA2-dependent manner. Together, our data reveal extensive, uncharted isoform and interaction complexity within the HSP70 network, and uncover isoform-dependent hetero-complex remodeling as a new layer of chaperone network regulation.
ER -