ER stress decreases exosome production through adiponectin/T-cadherin-dependent and -independent pathways.

Exosomes, extracellular vesicles (EVs) produced within cells, mediate both the disposal of intracellular waste and communication with distant cells, and they are involved in a variety of disease processes. Although disease modifications of exosome cargos have been well studied, it has been poorly investigated how disease processes, such as endoplasmic reticulum (ER) stress, affect EV production. We previously reported that adiponectin, an adipocyte-secreted salutary factor, increases systemic exosome levels through T-cadherin-mediated enhancement of exosome biogenesis. In the present study, we demonstrated that adiponectin/T-cadherin-dependent EV production was susceptible to ER stress and that low-dose tunicamycin significantly reduced EV production in the presence, but not in the absence, of adiponectin. Moreover, pharmacological or genetic activation of inositol-requiring enzyme 1α, a central regulator of ER stress, downregulated T-cadherin at the mRNA and protein levels as well as attenuated EV production. In addition, adiponectin/T-cadherin-independent EV production was attenuated under ER stress conditions. Repeated administration of tunicamycin to mice decreased circulating small EVs without decreasing tissue T-cadherin expression. Mechanistically, inositol-requiring enzyme 1α activation by silencing of the X-box binding protein 1 transcription factor upregulated the canonical interferon pathway and decreased EV production. The interferon pathway, when it was activated by polyinosinic-polycytidylic acid, also significantly attenuated EV production. Thus, we concluded that ER stress decreases exosome production through adiponectin/T-cadherin-dependent and -independent pathways. Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Keita Fukuoka, Ryohei Mineo, Shunbun Kita, Shiro Fukuda, Tomonori Okita, Emi Kawada-Horitani, Masahito Iioka, Kohei Fujii, Keitaro Kawada, Yuya Fujishima, Hitoshi Nishizawa, Norikazu Maeda, Iichiro Shimomura. ER stress decreases exosome production through adiponectin/T-cadherin-dependent and -independent pathways. The Journal of biological chemistry. 2023 Jul 29;299(9):105114

PMID: 37524131

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