Intercellular chaperone transmission via exosomes contributes to maintenance of protein homeostasis at the organismal level

Abstract

The heat shock response (HSR), a transcriptional response that upregulates molecular chaperones upon heat shock, is necessary for cell survival in a stressful environment to maintain protein homeostasis (proteostasis). However, there is accumulating evidence that the HSR does not ubiquitously occur under stress conditions, but largely depends on the cell types. Despite such imbalanced HSR among different cells and tissues, molecular mechanisms by which multicellular organisms maintain their global proteostasis have remained poorly understood. Here, we report that proteostasis can be maintained by molecular chaperones not only in a cell-autonomous manner but also in a non-cell-autonomous manner. We found that elevated expression of molecular chaperones, such as Hsp40 and Hsp70, in a group of cells improves proteostasis in other groups of cells, both in cultured cells and in Drosophila expressing aggregationprone polyglutamine proteins. We also found that Hsp40, as well as Hsp70 and Hsp90, is physiologically secreted from cells via exosomes, and that the J domain at the N terminus is responsible for its exosome-mediated secretion. Addition of Hsp40/Hsp70-containing exosomes to the culture medium of the polyglutamine-expressing cells results in efficient suppression of inclusion body formation, indicating that molecular chaperones non-cell autonomously improve the protein-folding environment via exosome-mediated transmission. Our study reveals that intercellular chaperone transmission mediated by exosomes is a novel molecular mechanism for non-cell-autonomous maintenance of organismal proteostasis that could functionally compensate for the imbalanced state of the HSR among different cells, and also provides a novel physiological role of exosomes that contributes to maintenance of organismal proteostasis. molecular chaperones | proteostasis | exosome | non-cell autonomous | polyglutamine

A Deep Proteome Analysis Identifies the Complete Secretome as the Functional Unit of Human Cardiac Progenitor Cells

“…76, 77 HSPs (chaperone proteins), which are known to be under the direct regulation of HSF1, were highly represented in nTCM as compared to aTCM (Figure 6G), we propose that the secretome can also transmit these chaperone proteins between cells via exosomes to maintain the proteostasis of the target cells. 78 HSF1 positively affects exosome production from CPCs, which are also an active composition of the secretome. 79 HSF1 is also known to reduce the effects of ageing, improve longevity, and strengthen elderly hearts against stress.…”

Dynamics of Heat Shock Detection and Response in the Intestine ofCaenorhabditis elegans

“…It also has a housekeeping functionality under normal conditions, helping to maintain protein folding under small thermal fluctuations (Balch et al, 2008;Somero, 1995). While the HSR pathway was originally thought to be cell-autonomous, more recent work provides evidence for additional layers of regulation and the involvement of multiple signaling pathways (Guisbert et al, 2013;Takeuchi et al, 2015;van Oosten-Hawle et al, 2013). A better understanding of the hierarchy of regulation of the HSR could lead to novel therapies for disease intervention (Bose & Cho, 2016;Balch et al, 2008;Westerheide & Morimoto, 2005;Prahlad & Morimoto, 2009).…”

Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective

“…For example, there is evidence that exercise promotes the release of extracellular HSP72 from certain human cells (brain [29]; epithelium [30]; immune system [31]; muscle and adipose tissue [32]). However, long-term exercise promotes a decrease in extracellular HSP72 and an increase in intracellular skeletal muscle HSP72 [28].…”