ER proteostasis regulators cell-non-autonomously control sleep
Taizo Kawano,
Mitsuaki Kashiwagi,
Mika Kanuka,
Chung-Kuan Chen,
Shinnosuke Yasugaki,
Sena Hatori,
Shinichi Miyazaki,
Kaeko Tanaka,
Hidetoshi Fujita,
Toshiro Nakajima,
Masashi Yanagisawa,
Yoshimi Nakagawa,
Yu Hayashi
Affiliations
Taizo Kawano
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba 305-8575, Japan
Mitsuaki Kashiwagi
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba 305-8575, Japan; Department of Biological Sciences, Graduate School of Science, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
Mika Kanuka
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba 305-8575, Japan
Chung-Kuan Chen
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba 305-8575, Japan; Doctoral Program in Biomedical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
Shinnosuke Yasugaki
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba 305-8575, Japan; Doctoral Program in Biomedical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
Sena Hatori
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba 305-8575, Japan; PhD Program in Humanics, School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
Shinichi Miyazaki
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba 305-8575, Japan; PhD Program in Humanics, School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
Kaeko Tanaka
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba 305-8575, Japan
Hidetoshi Fujita
Department of Biomedical Engineering, Osaka Institute of Technology, Osaka 535-8585, Japan
Toshiro Nakajima
Institute of Medical Science, Tokyo Medical University, Shinjuku-ku, Tokyo 160-8402, Japan
Masashi Yanagisawa
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba 305-8575, Japan; Life Science Center, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba 305-8575, Japan; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Yoshimi Nakagawa
Department of Complex Biosystem Research, Institute of Natural Medicine, University of Toyama, Toyama, Toyama 930-0194, Japan
Yu Hayashi
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba 305-8575, Japan; Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan; Department of Biological Sciences, Graduate School of Science, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan; Corresponding author
Summary: Sleep is regulated by peripheral tissues under fatigue. The molecular pathways in peripheral cells that trigger systemic sleep-related signals, however, are unclear. Here, a forward genetic screen in C. elegans identifies 3 genes that strongly affect sleep amount: sel-1, sel-11, and mars-1. sel-1 and sel-11 encode endoplasmic reticulum (ER)-associated degradation components, whereas mars-1 encodes methionyl-tRNA synthetase. We find that these machineries function in non-neuronal tissues and that the ER unfolded protein response components inositol-requiring enzyme 1 (IRE1)/XBP1 and protein kinase R-like ER kinase (PERK)/eukaryotic initiation factor-2α (eIF2α)/activating transcription factor-4 (ATF4) participate in non-neuronal sleep regulation, partly by reducing global translation. Neuronal epidermal growth factor receptor (EGFR) signaling is also required. Mouse studies suggest that this mechanism is conserved in mammals. Considering that prolonged wakefulness increases ER proteostasis stress in peripheral tissues, our results suggest that peripheral ER proteostasis factors control sleep homeostasis. Moreover, based on our results, peripheral tissues likely cope with ER stress not only by the well-established cell-autonomous mechanisms but also by promoting the individual’s sleep.
