Fine-tuning of mTOR signaling by the UBE4B-KLHL22 E3 ubiquitin ligase cascade in brain development

Kong, Xiangxing; Shu, Xin; Wang, Jiachuan; Liu, Dandan; Ni, Yingchun; Zhao, Weiqi; Wang, Lebo; Gao, Zhihua; Chen, Jiadong; Yang, Bing; Guo, Xing; Wang, Zhiping

doi:10.1242/dev.201286

Fine-tuning of mTOR signaling by the UBE4B-KLHL22 E3 ubiquitin ligase cascade in brain development

Journal Article · Tue Dec 20 00:00:00 EST 2022 · Development (Cambridge)

DOI:https://doi.org/10.1242/dev.201286· OSTI ID:1905927

Kong, Xiangxing; Shu, Xin; ; Liu, Dandan; Ni, Yingchun; Zhao, Weiqi; Wang, Lebo; ; ; ; ;

ABSTRACT

Spatiotemporal regulation of the mechanistic target of rapamycin (mTOR) pathway is pivotal for establishment of brain architecture. Dysregulation of mTOR signaling is associated with a variety of neurodevelopmental disorders. Here, we demonstrate that the UBE4B-KLHL22 E3 ubiquitin ligase cascade regulates mTOR activity in neurodevelopment. In a mouse model with UBE4B conditionally deleted in the nervous system, animals display severe growth defects, spontaneous seizures and premature death. Loss of UBE4B in the brains of mutant mice results in depletion of neural precursor cells and impairment of neurogenesis. Mechanistically, UBE4B polyubiquitylates and degrades KLHL22, an E3 ligase previously shown to degrade the GATOR1 component DEPDC5. Deletion of UBE4B causes upregulation of KLHL22 and hyperactivation of mTOR, leading to defective proliferation and differentiation of neural precursor cells. Suppression of KLHL22 expression reverses the elevated activity of mTOR caused by acute local deletion of UBE4B. Prenatal treatment with the mTOR inhibitor rapamycin rescues neurogenesis defects in Ube4b mutant mice. Taken together, these findings demonstrate that UBE4B and KLHL22 are essential for maintenance and differentiation of the precursor pool through fine-tuning of mTOR activity.

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Sponsoring Organization:: USDOE Office of Electricity (OE), Advanced Grid Research & Development. Power Systems Engineering Research

OSTI ID:: 1905927

Journal Information:: Development (Cambridge), Journal Name: Development (Cambridge) Journal Issue: 24 Vol. 149; ISSN 0950-1991

Publisher:: The Company of BiologistsCopyright Statement

Country of Publication:: United Kingdom

Language:: English

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