KBG syndrome-associated protein ANKRD11 regulates SETD5 expression to modulate rRNA levels and translation
Shoko Sashiyama,
Tadashi Nakagawa,
Makiko Nakagawa,
Masaki Hosogane,
Yasuaki Watanabe,
Honoka Ashitomi,
Kazusa Yamane,
Norihiro Shibuya,
Toshiro Moroishi,
Keiko Nakayama,
Toru Hosoi
Affiliations
Shoko Sashiyama
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Sanyo-Onoda 756-0884, Japan; Department of Molecular and Medical Pharmacology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
Tadashi Nakagawa
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Sanyo-Onoda 756-0884, Japan; Division of Cell Proliferation, ART, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan; Corresponding author
Makiko Nakagawa
Division of Cell Proliferation, ART, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan; Institute of Gene Research, Yamaguchi University Science Research Center, Ube 755-8505, Japan; Advanced Technology Institute, Life Science Division, Yamaguchi University, Yamaguchi 755-8611, Japan
Masaki Hosogane
Division of Cell Proliferation, ART, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan
Yasuaki Watanabe
Division of Cell Proliferation, ART, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan; Department of Neurology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
Honoka Ashitomi
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Sanyo-Onoda 756-0884, Japan
Kazusa Yamane
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Sanyo-Onoda 756-0884, Japan
Norihiro Shibuya
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Sanyo-Onoda 756-0884, Japan
Toshiro Moroishi
Department of Molecular and Medical Pharmacology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; Center for Metabolic Regulation of Healthy Aging, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; Division of Cellular Dynamics, Medical Research Laboratory, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
Keiko Nakayama
Division of Cell Proliferation, ART, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan; Research Infrastructure Management Center, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
Toru Hosoi
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Sanyo-Onoda 756-0884, Japan
Summary: ANKRD11 haploinsufficiency is implicated in KBG syndrome, characterized by intellectual disability, autism spectrum disorders, and skeletal abnormalities. While SETD5 mutations are linked to a distinct clinical disorder, they also appear in KBG-like cases, suggesting shared molecular pathways. Here, we show that ANKRD11-deficient neural cells exhibit reduced ribosomal RNA (rRNA) and translation. Although ANKRD11 primarily localizes outside the nucleolus, where rDNA transcription occurs, it indirectly promotes rRNA expression by upregulating SETD5, a transcriptional activator of rRNA. Mechanistically, ANKRD11 interacts with the Setd5 promoter and recruits WDR5, a component of the histone H3 lysine 4 (H3K4) methyltransferase complex involved in transcriptional activation. Correspondingly, reduced H3K4 methylation on the Setd5 promoter correlates with diminished SETD5 expression in ANKRD11-deficient cells. Overexpression of ANKRD11 or SETD5 restores rRNA levels and translational activity. These findings underscore the role of the ANKRD11-SETD5 axis in alleviating KBG syndrome pathogenesis, offering insights into potential therapeutic targets.
