PXD035852-1

PXD035852 is an original dataset announced via ProteomeXchange.

Title	Fine-tuning of mTOR signaling by the UBE4B-KLHL22 E3 ubiquitin ligase cascade in brain development
Description	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 (NDDs). Here, we discover 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 (NPCs), impairment of neurogenesis, and enlargement of neuronal soma. Mechanistically, UBE4B polyubiquitinates 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 NPCs. Suppression of KLHL22 expression reverses the elevated activity of mTOR caused by acute local deletion of UBE4B in the dentate gyrus (DG). 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.
HostingRepository	PRIDE
AnnounceDate	2022-12-12
AnnouncementXML	Submission_2022-12-12_05:59:57.396.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	XinShu
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	acetylated residue; monohydroxylated residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2022-08-07 03:42:15	ID requested
⏵ 1	2022-12-12 05:59:57	announced
2	2023-11-14 08:57:15	announced	2023-11-14: Updated project metadata.

submitter keyword: Mouse brain,MS,UBE4B

Xiang_XingKong
contact affiliation	ZJU
contact email	11718017@zju.edu.cn
lab head
XinShu
contact affiliation	Zhejiang university
contact email	sx725@zju.edu.cn
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD035852
     1. Label: PRIDE project
     2. Name: Fine-tuning of mTOR signaling by the UBE4B-KLHL22 E3 ubiquitin ligase cascade in brain development