Skip to content
DraconiticResearch
Search Sources API
181,686 studies31 sourcesUpdated 13 min ago
Peer-reviewedCC BY 4.0Cell Communication and Signaling : CCS

BTBD9-driven IMPDH2 ubiquitination governs sleep homeostasis by gating adenosine metabolism in the basal forebrain

  • Zhenfei Gao1,2
  • Niannian Li1,2
  • Jiawei Feng1,2
  • Jinhong Shen1,2
  • Haolin Yuan1,2
  • Kejia Wu1,2
  • Xu Xu1,2
  • Yuenan Liu3
  • Yiming Hu1,2
  • Shengming Wang1,2
  • Hui Wang1,2
  • Xiangshan Yuan4
3 more authors
  • Jian Guan1,2
  • Feng Liu1,2
  • Shankai Yin1,2
4 affiliations
  1. 1Department of Otolaryngology-Head and Neck Surgery & Center of Sleep Medicine, Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai Jiao Tong University School of Medicine Affiliated Sixth People’s Hospital, Shanghai, 200233 China
  2. 2Center for Sleep Monitoring and Respiratory Therapy Technology, Institute of Medical Equipment and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200233 China
  3. 3Department of Otolaryngology & Head and Neck Surgery, School of Medicine, Ruijin Hospital, Shanghai Jiao Tong University, No. 197 Ruijin 2nd Road, Shanghai, 200025 China
  4. 4Department of Anatomy and Histoembryology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032 China
Read full textDOICite

Abstract

Background: BTB domain containing 9 (BTBD9) is among the most reproducible genetic risk factors for sleep-related disorders, yet its molecular function in sleep regulation remains unclear. Here, we aimed to define the downstream substrate, core brain region, and molecular mechanism through which BTBD9 regulates sleep–wake homeostasis.

Methods: Population-scale genomic and brain expression quantitative trait locus (eQTL) datasets were integrated to infer the direction of BTBD9-associated genetic risk in sleep-related traits. Basal forebrain-specific neuronal manipulation of Btbd9 was combined with electroencephalography/electromyography (EEG/EMG)-based sleep analysis and fiberphotomerty to define the relevant brain locus and functional output. Ubiquitinomics, protein interaction, ubiquitination, and enzymatic assays were used to identify BTBD9-regulated substrates and determine how BTBD9-dependent modification affects metabolic enzyme activity. Basal forebrain-specific genetic disruption, receptor pharmacology, and adeno-associated virus (AAV)-delivered interfering peptides were further applied to test pathway necessity and reversibility in vivo.

Results: human genetic analyses showed that BTBD9 variants associated with higher expression predicted a pro-arousal tendency. Consistently, neuron-specific deletion of Btbd9 in the mouse basal forebrain increased non-rapid eye movement (NREM) sleep and extracellular adenosine levels. Mechanistically, IMPDH2, the rate-limiting enzyme in de novo purine biosynthesis, was identified as a substrate of the Cullin-RING E3 ubiquitin ligase 3 (CRL3)BTBD9 ubiquitin ligase. BTBD9-mediated ubiquitination at IMPDH2 lysine 195 (K195) relieved guanosine triphosphate (GTP)-dependent allosteric inhibition, thereby limiting adenosine accumulation and sleep pressure. Basal forebrain neuronal knockout of Impdh2 recapitulated the sleep-promoting effect of Btbd9 deletion, whereas adenosine A1 receptor (A1R) blockade attenuated this phenotype. AAV-delivered interfering peptides targeting the BTBD9–IMPDH2 interaction reduced IMPDH2 ubiquitination, elevated adenosine levels, increased NREM sleep, and rescued BTBD9 overexpression-induced abnormal wakefulness in vivo.

Conclusions: These findings identify a BTBD9–IMPDH2–adenosine pathway that links human genetic risk to basal forebrain control of sleep homeostasis. By defining BTBD9 as a molecular regulator of purine metabolism, this study provides a mechanistic framework for understanding and potentially targeting BTBD9-related sleep dysregulation.

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12964-026-03117-2.

Related

  1. Cross-regulatory sRNA networks shape adaptive stress responses in Staphylococcus aureus: RsaC and RsaOI regulate galactose metabolism and cell wall homeostasis
    H. ROBIN, M. GERMAIN, C. SILARD +4
    bioRxivPreprintAll rights reservedFull textMicrobiologybioRxiv
  2. Maternal gut microbiota, tryptophan metabolism and immune homeostasis: Implications for the prevention of adverse pregnancy complications
    Chenjun Wang, Siyu Wu, Biyan He +9
    iSciencePeer-reviewedCC BY-NC-ND 4.0Developmental biologyImmunologyCell PressCrossref
  3. PqqU (PA2289) is the primary PQQ transporter in Pseudomonas aeruginosa and links carbon metabolism to iron homeostasis
    Christos Paschalidis, Manon Ferry, Anne-Eloïse Revillot- -Schmidt +6
    FEMS Microbiology LettersPeer-reviewedCC BY 4.0Full textGeneral biologyHAL
  4. FE DEFICIENCY-INDUCED KELCH REPEAT PROTEIN 1 (FDK1) links coumarin metabolism and iron homeostasis during alkaline iron deficiency in Arabidopsis
    H.-J. Mai, C. von der Mark, J. C. Lucas +8
    bioRxivPreprintCC BY-NDFull textPlant biologybioRxiv
  5. Elucidating the role of glucose-mediated redox homeostasis, carbohydrate metabolism, and secondary metabolite production in enhancing photosynthetic activity, ionomics, and yield in two okra (Abelmoschus esculentus) varieties
    Yamshi Arif, Saif Ahmad, Priyanka Singh +4
    Frontiers in Plant SciencePeer-reviewedCC BY 4.0Plant biologyFrontiersCrossref

Cite

BibTeXRIS
BibTeX
@article{gao2026btbd9driven,
  title = {{BTBD9-driven IMPDH2 ubiquitination governs sleep homeostasis by gating adenosine metabolism in the basal forebrain}},
  author = {Zhenfei Gao and Niannian Li and Jiawei Feng and Jinhong Shen and Haolin Yuan and Kejia Wu and Xu Xu and Yuenan Liu and Yiming Hu and Shengming Wang and Hui Wang and Xiangshan Yuan and Jian Guan and Feng Liu and Shankai Yin},
  journal = {Cell Communication and Signaling : CCS},
  year = {2026},
  month = jul,
  doi = {10.1186/s12964-026-03117-2},
  url = {https://doi.org/10.1186/s12964-026-03117-2},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - BTBD9-driven IMPDH2 ubiquitination governs sleep homeostasis by gating adenosine metabolism in the basal forebrain
AU  - Zhenfei Gao
AU  - Niannian Li
AU  - Jiawei Feng
AU  - Jinhong Shen
AU  - Haolin Yuan
AU  - Kejia Wu
AU  - Xu Xu
AU  - Yuenan Liu
AU  - Yiming Hu
AU  - Shengming Wang
AU  - Hui Wang
AU  - Xiangshan Yuan
AU  - Jian Guan
AU  - Feng Liu
AU  - Shankai Yin
PY  - 2026
DA  - 2026/07/30
JO  - Cell Communication and Signaling : CCS
DO  - 10.1186/s12964-026-03117-2
UR  - https://doi.org/10.1186/s12964-026-03117-2
AB  - Background: BTB domain containing 9 (BTBD9) is among the most reproducible genetic risk factors for sleep-related disorders, yet its molecular function in sleep regulation remains unclear. Here, we aimed to define the downstream substrate, core brain region, and molecular mechanism through which BTBD9 regulates sleep–wake homeostasis.  Methods: Population-scale genomic and brain expression quantitative trait locus (eQTL) datasets were integrated to infer the direction of BTBD9-associated genetic risk in sleep-related traits. Basal forebrain-specific neuronal manipulation of Btbd9 was combined with electroencephalography/electromyography (EEG/EMG)-based sleep analysis and fiberphotomerty to define the relevant brain locus and functional output. Ubiquitinomics, protein interaction, ubiquitination, and enzymatic assays were used to identify BTBD9-regulated substrates and determine how BTBD9-dependent modification affects metabolic enzyme activity. Basal forebrain-specific genetic disruption, receptor pharmacology, and adeno-associated virus (AAV)-delivered interfering peptides were further applied to test pathway necessity and reversibility in vivo.  Results: human genetic analyses showed that BTBD9 variants associated with higher expression predicted a pro-arousal tendency. Consistently, neuron-specific deletion of Btbd9 in the mouse basal forebrain increased non-rapid eye movement (NREM) sleep and extracellular adenosine levels. Mechanistically, IMPDH2, the rate-limiting enzyme in de novo purine biosynthesis, was identified as a substrate of the Cullin-RING E3 ubiquitin ligase 3 (CRL3)BTBD9 ubiquitin ligase. BTBD9-mediated ubiquitination at IMPDH2 lysine 195 (K195) relieved guanosine triphosphate (GTP)-dependent allosteric inhibition, thereby limiting adenosine accumulation and sleep pressure. Basal forebrain neuronal knockout of Impdh2 recapitulated the sleep-promoting effect of Btbd9 deletion, whereas adenosine A1 receptor (A1R) blockade attenuated this phenotype. AAV-delivered interfering peptides targeting the BTBD9–IMPDH2 interaction reduced IMPDH2 ubiquitination, elevated adenosine levels, increased NREM sleep, and rescued BTBD9 overexpression-induced abnormal wakefulness in vivo.  Conclusions: These findings identify a BTBD9–IMPDH2–adenosine pathway that links human genetic risk to basal forebrain control of sleep homeostasis. By defining BTBD9 as a molecular regulator of purine metabolism, this study provides a mechanistic framework for understanding and potentially targeting BTBD9-related sleep dysregulation.  Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12964-026-03117-2.
SN  - 1478-811X
ER  -