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Nat. Commun., Published: 18 March 2025 | https://doi.org/10.1038/s41467-025-57793-8
HSD17B4 deficiency causes dysregulation of primary cilia and is alleviated by acetyl-CoA
Ji-Eun Bae1,7, Soyoung Jang1,2,7, Joon Bum Kim2, Na Yeon Park1,2, Doo Sin Jo3, Hyejin Hyung2, Pansoo Kim3, Min-Seon Kim4, Hong-Yeoul Ryu2,5, Hyun-Shik Lee2,5, Dong-Seok Lee2, Myriam Baes6, Zae Young Ryoo2 & Dong-Hyung Cho1,2,3
1Organelle Institute, Kyungpook National University, Daegu, Republic of Korea.
2School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea.
3ORGASIS Corp, Suwon, Gyeonggi-do, Republic of Korea.
4Division of Endocrinology and Metabolism, Asan Medical Center, Seoul, Republic of Korea.
5KNU G-LAMP Project Group, KNU Institute of Basic Sciences, Kyungpook National University, Daegu, Republic of Korea.
6Laboratory of Cell Metabolism, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
7These authors contributed equally: Ji-Eun Bae, Soyoung Jang.
Corresponding authors
Correspondence to Zae Young Ryoo or Dong-Hyung Cho.
1Organelle Institute, Kyungpook National University, Daegu, Republic of Korea.
2School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea.
3ORGASIS Corp, Suwon, Gyeonggi-do, Republic of Korea.
4Division of Endocrinology and Metabolism, Asan Medical Center, Seoul, Republic of Korea.
5KNU G-LAMP Project Group, KNU Institute of Basic Sciences, Kyungpook National University, Daegu, Republic of Korea.
6Laboratory of Cell Metabolism, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
7These authors contributed equally: Ji-Eun Bae, Soyoung Jang.
Corresponding authors
Correspondence to Zae Young Ryoo or Dong-Hyung Cho.
Abstract
Primary cilia are dynamic sensory organelles orchestrating key signaling pathways, and disruption of primary ciliogenesis is implicated in a spectrum of genetic disorders. The peroxisomal bifunctional enzyme HSD17B4 is pivotal for peroxisomal β-oxidation and acetyl-CoA synthesis, and its deficiency profoundly impairs peroxisomal metabolism. While patients with HSD17B4 deficiency exhibit ciliopathy-like symptoms due to dysfunctional primary cilia, the molecular connection between HSD17B4 and ciliopathy remains poorly understood. Here, we demonstrate that HSD17B4 deficiency impairs primary ciliogenesis and alters cilia-mediated signaling, suggesting a potential link between peroxisomal metabolism and ciliary function. Notably, elevation of acetyl-CoA rescues ciliary defects via HDAC6-mediated ciliogenesis in HSD17B4-deficient cells. Strikingly, acetate administration restores motor function, enhances primary cilia formation, and preserves the Purkinje layer in Hsd17B4-knockout mice. These findings provide insights into the functional link between HSD17B4 and primary cilia, highlighting acetyl-CoA as a potential therapeutic target for HSD17B4 deficiency and ciliopathy.
논문정보
- Research article
- 2025년 03월 (BRIC 등록일 2025-03-19)
- 국내(교신)+국외 연구진
- 생명과학 > 세포생물학
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