PXD053163

PXD053163 is an original dataset announced via ProteomeXchange.

Title	Amelioration of nonalcoholic fatty liver disease by inhibiting the deubiquitylating enzyme RPN11
Description	Nonalcoholic fatty liver disease (NAFLD) including its more severe manifestation, nonalcoholic steatohepatitis (NASH), is a global public health challenge. Here, we reveal a role for the deubiquitinating enzyme RPN11 in the development of NAFLD and NASH. Ablation of hepatic RPN11 markedly protected mice from several diets-induced liver steatosis, insulin resistance and steatohepatitis, whereas RPN11 overexpression had the opposite effects. Mechanistically, RPN11 interacts with and stabilizes METTL3 via deubiquitination initiated at lysine 241, to increase the m6A modification and expression of acyl-CoA synthetase short chain family member 3 (ACSS3). RPN11-ACSS3 axis generates propionyl-CoA and functions in histone propionylation to transcriptionally upregulate lipid metabolism-related genes. Of pathophysiological significance, RPN11-METTL3-ACSS3-histone propionylation modification pathway is activated in the livers of patients with NAFLD. More importantly, pharmacological inhibition of RPN11 by Capzimin showed dramatic beneficial effects in ameliorating NAFLD, NASH and related metabolic disorders in mice. Capzimin also reduces intracellular lipid contents in human primary hepatocytes cultured in 2D and 3D spheroids. Together, these results demonstrate that RPN11 is a novel regulator of NAFLD/NASH and that suppressing RPN11 has therapeutic potential for the treatment.
HostingRepository	iProX
AnnounceDate	2024-06-15
AnnouncementXML	Submission_2024-12-12_19:02:51.635.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Bing Zhou
SpeciesList	scientific name: Mus musculus; NCBI TaxID: 10090; scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2024-06-16 23:54:14	ID requested
⏵ 1	2024-12-12 19:02:52	announced

Zhou B, Luo Y, Bi H, Zhang N, Ma M, Dong Z, Ji N, Zhang S, Wang X, Liu Y, Guo X, Wei W, Xie C, Wu L, Wan X, Zheng MH, Zhao B, Li Y, Hu C, Lu Y, Amelioration of nonalcoholic fatty liver disease by inhibiting the deubiquitylating enzyme RPN11. Cell Metab, 36(10):2228-2244.e7(2024) [pubmed]

submitter keyword: Nonalcoholic fatty liver disease, Nonalcoholic steatohepatitis, Deubiquitination, N6-methyladenosine methylation, Histone propionylation

Yan Lu
contact affiliation	Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
contact email	luyan5011@shsmu.edu.cn
lab head
Bing Zhou
contact affiliation	Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
contact email	zhoub23@mail2.sysu.edu.cn
dataset submitter

iProX dataset URI