Rhomboid protease RHBDL4/RHBDD1 cleaves SREBP-1c at endoplasmic reticulum monitoring and regulating fatty acids

Song-Iee Han; Masanori Nakakuki; Yoshimi Nakagawa; Yunong Wang; Masaya Araki; Yuta Yamamoto; Hiroaki Tokiwa; Hiroyuki Takeda; Yuhei Mizunoe; Kaori Motomura; Hiroshi Ohno; Kenta Kainoh; Yuki Murayama; Yuichi Aita; Yoshinori Takeuchi; Yoshinori Osaki; Takafumi Miyamoto; Motohiro Sekiya; Takashi Matsuzaka; Naoya Yahagi; Hirohito Sone; Hiroaki Daitoku; Ryuichiro Sato; Hiroyuki Kawano; Hitoshi Shimano

doi:10.1093/pnasnexus/pgad351

Rhomboid protease RHBDL4/RHBDD1 cleaves SREBP-1c at endoplasmic reticulum monitoring and regulating fatty acids

PNAS Nexus. 2023 Nov 8;2(11):pgad351. doi: 10.1093/pnasnexus/pgad351. eCollection 2023 Nov.

Authors

Song-Iee Han^{1

2}, Masanori Nakakuki³, Yoshimi Nakagawa^{1

4}, Yunong Wang¹, Masaya Araki¹, Yuta Yamamoto⁵, Hiroaki Tokiwa⁶, Hiroyuki Takeda⁷, Yuhei Mizunoe¹, Kaori Motomura¹, Hiroshi Ohno¹, Kenta Kainoh¹, Yuki Murayama¹, Yuichi Aita¹, Yoshinori Takeuchi¹, Yoshinori Osaki¹, Takafumi Miyamoto^{1

8}, Motohiro Sekiya¹, Takashi Matsuzaka^{1

8}, Naoya Yahagi¹, Hirohito Sone⁹, Hiroaki Daitoku¹⁰, Ryuichiro Sato¹¹, Hiroyuki Kawano³, Hitoshi Shimano^{1

2

10

12}

Affiliations

¹ Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
² International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
³ Pharmaceutical Research Center, Mochida Pharmaceutical Co., Ltd., Gotemba, Shizuoka 412-8524, Japan.
⁴ Division of Complex Biosystem Research, Department of Research and Development, Institute of Natural Medicine, University of Toyama, Toyama, Toyama 930-0194, Japan.
⁵ Department of Chemistry, Rikkyo University, Toshima-ku, Tokyo 171-8501, Japan.
⁶ Laboratory of Organic Chemistry, Gifu Pharmaceutical University, Daigaku-Nishi, Gifu 501-1196, Japan.
⁷ Division of Proteo Drug Discovery Sciences, Proteo-Science Center, Ehime University, Matsuyama, Ehime 790-8577, Japan.
⁸ Transborder Medical Research Center, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.
⁹ Department of Internal Medicine, Faculty of Medicine, Niigata University, Niigata, Niigata 951-8510, Japan.
¹⁰ Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.
¹¹ Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, Nutri-Life Science Laboratory, The University of Tokyo, Tokyo 113-8657, Japan.
¹² Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Chiyoda-ku, Tokyo 100-0004, Japan.

Abstract

The endoplasmic reticulum (ER)-embedded transcription factors, sterol regulatory element-binding proteins (SREBPs), master regulators of lipid biosynthesis, are transported to the Golgi for proteolytic activation to tune cellular cholesterol levels and regulate lipogenesis. However, mechanisms by which the cell responds to the levels of saturated or unsaturated fatty acids remain underexplored. Here, we show that RHBDL4/RHBDD1, a rhomboid family protease, directly cleaves SREBP-1c at the ER. The p97/VCP, AAA-ATPase complex then acts as an auxiliary segregase to extract the remaining ER-embedded fragment of SREBP-1c. Importantly, the enzymatic activity of RHBDL4 is enhanced by saturated fatty acids (SFAs) but inhibited by polyunsaturated fatty acids (PUFAs). Genetic deletion of RHBDL4 in mice fed on a Western diet enriched in SFAs and cholesterol prevented SREBP-1c from inducing genes for lipogenesis, particularly for synthesis and incorporation of PUFAs, and secretion of lipoproteins. The RHBDL4-SREBP-1c pathway reveals a regulatory system for monitoring fatty acid composition and maintaining cellular lipid homeostasis.

Keywords: PUFA; RHBDL4; SREBP-1c; p97/VCP.