Nervous System Integrity in Drosophila: Essential and Dosage-Sensitive Roles of Hsp110

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ID: 327786
2026
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Abstract
The Hsp70 chaperone system is central in maintaining cellular proteostasis. In eukaryotes, its ATP/ADP nucleotide exchange cycle is stimulated by co-chaperone Hsp110, a divergent Hsp70 superfamily member and a modifier of protein misfolding disorders. Hsp110 chaperone functions and pathway interactions have been extensively characterized biochemically in vitro and genetically in yeast models; however, its physiological roles in metazoans, particularly in the nervous system, are lacking. Here, we showed that the single Hsp110 gene in Drosophila share significant sequence, structural, and splicing-variant similarities with human Hsp110. In Drosophila, Hsp110 is ubiquitously expressed and dispensable for cell proliferation in developing larvae, but is essential for long-term cell survival and nervous system development, including non-autonomous effects on neuronal differentiation and glial cell migration. Furthermore, loss of Hsp110 leads to abnormal accumulation of ubiquitin-positive inclusions in the brain. Lastly, despite being identified as a potent suppressor of protein aggregation and neurotoxicity in neurodegenerative diseases, higher levels of Hsp110 are detrimental in flies. Overexpression of Hsp40, another key co-chaperone of Hsp70, can mimic this effect. However, simultaneous overexpression of both Hsp40 and Hsp110 does not further exacerbate their detrimental effect. Together, these results demonstrate a critical role of Hsp110 in cellular proteostasis, neuronal development, and cell survival in metazoans, and suggest that in vivo, the levels and activities of Hsp110 and Hsp40 co-chaperones need to be properly balanced, and the Hsp70 chaperone network should be considered as a whole when targeted for potential therapeutic purposes to meet the complex pathophysiological demands in multicellular organisms.
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Authors Beatriz Rios, Shiyu Xu, Stephen M. Farmer, Xin Ye, Lili Ye, Kevin A. Morano, Sheng Zhang
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Journal current genetics
Year 2026
DOI
10.1093/genetics/iyag240
URL
https://doi.org/10.1093/genetics/iyag240
Keywords Keywords not found

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