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

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 YahagiHirohito Sone, Hiroaki Daitoku, Ryuichiro Sato, Hiroyuki Kawano, Hitoshi Shimano^*

^*Corresponding author for this work

Complex Biosystem Research, Institute of Natural Medicine

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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.

Original language	English
Article number	2
Journal	PNAS nexus
Volume	2
Issue number	11
DOIs	https://doi.org/10.1093/pnasnexus/pgad351
State	Published - 2023/11/01

Keywords

PUFA
RHBDL4
SREBP-1c
p97/VCP

ASJC Scopus subject areas

General

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10.1093/pnasnexus/pgad351

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Han, S. I., Nakakuki, M., Nakagawa, Y., Wang, Y., Araki, M., Yamamoto, Y., Tokiwa, H., Takeda, H., Mizunoe, Y., Motomura, K., Ohno, H., Kainoh, K., Murayama, Y., Aita, Y., Takeuchi, Y., Osaki, Y., Miyamoto, T., Sekiya, M., Matsuzaka, T., ... Shimano, H. (2023). Rhomboid protease RHBDL4/RHBDD1 cleaves SREBP-1c at endoplasmic reticulum monitoring and regulating fatty acids. PNAS nexus, 2(11), Article 2. https://doi.org/10.1093/pnasnexus/pgad351

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

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.",

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

year = "2023",

month = nov,

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doi = "10.1093/pnasnexus/pgad351",

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Han, SI, Nakakuki, M, Nakagawa, Y, Wang, Y, Araki, M, Yamamoto, Y, Tokiwa, H, Takeda, H, Mizunoe, Y, Motomura, K, Ohno, H, Kainoh, K, Murayama, Y, Aita, Y, Takeuchi, Y, Osaki, Y, Miyamoto, T, Sekiya, M, Matsuzaka, T, Yahagi, N, Sone, H, Daitoku, H, Sato, R, Kawano, H & Shimano, H 2023, 'Rhomboid protease RHBDL4/RHBDD1 cleaves SREBP-1c at endoplasmic reticulum monitoring and regulating fatty acids', PNAS nexus, vol. 2, no. 11, 2. https://doi.org/10.1093/pnasnexus/pgad351

TY - JOUR

T1 - Rhomboid protease RHBDL4/RHBDD1 cleaves SREBP-1c at endoplasmic reticulum monitoring and regulating fatty acids

AU - Han, Song Iee

AU - Nakakuki, Masanori

AU - Nakagawa, Yoshimi

AU - Wang, Yunong

AU - Araki, Masaya

AU - Yamamoto, Yuta

AU - Tokiwa, Hiroaki

AU - Takeda, Hiroyuki

AU - Mizunoe, Yuhei

AU - Motomura, Kaori

AU - Ohno, Hiroshi

AU - Kainoh, Kenta

AU - Murayama, Yuki

AU - Aita, Yuichi

AU - Takeuchi, Yoshinori

AU - Osaki, Yoshinori

AU - Miyamoto, Takafumi

AU - Sekiya, Motohiro

AU - Matsuzaka, Takashi

AU - Yahagi, Naoya

AU - Sone, Hirohito

AU - Daitoku, Hiroaki

AU - Sato, Ryuichiro

AU - Kawano, Hiroyuki

AU - Shimano, Hitoshi

PY - 2023/11/1

Y1 - 2023/11/1

N2 - 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.

AB - 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.

KW - PUFA

KW - RHBDL4

KW - SREBP-1c

KW - p97/VCP

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U2 - 10.1093/pnasnexus/pgad351

DO - 10.1093/pnasnexus/pgad351

M3 - 学術論文

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AN - SCOPUS:85177834781

SN - 2752-6542

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ER -

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

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Keywords

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