Investigation of the ER-related degradation zone and the mitochondria-ER communication zone
Various stresses from inside and outside of the cell induce the accumulation of unfolded proteins and cause cellular dysfunction in the endoplasmic reticulum (ER). Cells maintain the endoplasmic reticulum homeostasis by the activation of unfolded protein response (UPR). We will conduct the researches on the following two points related to the endoplasmic reticulum.
<Research on the ER-related degradation zone>
In addition to the ER-associated degradation (ERAD), ER stress-induced pre-emptive quality control (ERpQC) helps alleviate the burden to a stressed ER by limiting further protein load. We have reported the molecular mechanisms of ERpQC, which is composed of a rerouting step and a degradation step (Kadowaki et al, Cell Rep. 2015 and Sci. Rep. 2018). In a rerouting step, under ER stress condition, specific ER-targeting newly synthesized proteins are rerouted from the ER to the cytosol without cleavage of their signal peptides via the association of signal recognition particle, translocon and ERAD components. In a degradation step, the rerouted newly synthesized-polypeptides are ubiquitinated by HRD1, and transported to the proteasome via activities of Bag6 and p97. In this project, we clarify that there are different degradation zones related to ERAD and ERpQC.
<Research on the mitochondria-ER communication zone>
Mitochondria play a central role in the function of brown adipocytes. Although mitochondrial biogenesis is regulated by the coordination between nuclear DNA-mediated transcription and mitochondrial DNA-mediated transcription, the molecular mechanisms of mitochondrial development during brown adipocyte differentiation are largely unknown. Recently, we found the importance of mitochondria-ER crosstalk signaling in mitochondrial development and function in brown adipocytes. We aim to elucidate the molecular mechanism and the biological significance of stress response in the mitochondria-ER zone.
Kato, H., Okabe, K., Miyake, M., Hattori, K., Fukaya, T., Tanimoto, K., Beini, S., Mizuguchi, M., Torii, S., Arakawa, S., Ono, M., Saito, Y., Sugiyama, T., Funatsu, T., Sato, K., Shimizu, S., Oyadomari, S., Ichijo, H., Kadowaki, H., Nishitoh, H. (2020) ER-resident sensor PERK is essential for mitochondrial thermogenesis in brown adipose tissue. Life Sci. Alliance DOI:10.26508/lsa.201900576
- Tatenaka, Y., Kato, H., Ishiyama, M., Sasamoto, K., Shiga, M., Nishitoh, H., Ueno, Y. (2019) Monitoring lipid droplet dynamics in living cells by using fluorescent probes. Biochemistry 58:499-503.
- Kadowaki, H., Satrimafitrah, P., Takami, Y. and Nishitoh, H. (2018) Molecular mechanism of ER stress-induced pre-emptive quality control involving association of the translocon, Derlin-1, and HRD1. Sci. Rep., 8, 7317 | DOI:10.1038/s41598-018-25724-x
- Fujisawa, T., Takahashi, M., Tsukamoto, Y., Yamaguchi, N., Nakoji, M., Endo, M., Kodaira, H., Hayashi, Y., Nishitoh, H., Naguro, I., Homma, K., and Ichijo, H. (2016) The ASK1-specific inhibitors K811 and K812 prolong survival in a mouse model of amyotrophic lateral sclerosis. Hum. Mol. Genet. 25, 245-253
- Kadowaki, H., Nagai, A., Maruyama, T., Takami, Y., Satrimafitrah, P., Kato, H., Honda, A., Hatta, T., Natsume, T., Sato, T., Kai, H., Ichijo, H., and Nishitoh, H. (2015) Pre-emptive Quality Control Protects the ER from Protein Overload via the Proximity of ERAD Components and SRP. Cell Rep. 13, 944-956
- Homma, K., Fujisawa, T., Tsuburaya, N., Yamaguchi, N., Kadowaki, H., Takeda, K., Nishitoh, H., Matsuzawa, A., Naguro, I., and Ichijo, H. (2013) SOD1 as a molecular switch for initiating the homeostatic ER stress response under zinc deficiency. Mol. Cell 52, 75-86
- Nishitoh, H., Kadowaki, H., Nagai, A., Maruyama, T., Yokota, T., Fukutomi, H., Noguchi, T., Matsuzawa, A., Takeda, K., and Ichijo, H. (2008) ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1. Genes Dev. 22, 1451-1464
- Nishitoh, H., Matsuzawa, A., Tobiume, K., Saegusa, K., Takeda, K., Inoue, K., Hori, S., Kakizuka, A., and Ichijo, H. (2002) ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev. 16, 1345-1355
Nishitoh, H. (2019) Paradigm shift from “Compartment” to “Zone” in the understanding of organelles. J Biochem. 165, 97–99.
Kadowaki, H. and Nishitoh, H. (2019) Endoplasmic reticulum quality control by garbage disposal. FEBS J. 286:232-240.
- Murao, N., and Nishitoh, H. (2017) Role of the unfolded protein response in the development of central nervous system. J. Biochem. 162, 155-162
- Kato, H., and Nishitoh, H. (2015) Stress responses from the endoplasmic reticulum in cancer. Front. Oncol. 5, 93
- Kadowaki, H., and Nishitoh, H. (2013) Signaling pathways from the endoplasmic reticulum and their roles in disease. Genes 4, 306-333
- Nishitoh, H. (2012) CHOP is a multifunctional transcription factor in the ER stress response. J. Biochem. 151, 217-219