PXD038538

PXD038538 is an original dataset announced via ProteomeXchange.

Title	Deacetylation of Septin4 by NAD-dependent deacetylase SIRT2 mitigates damaging effects of hypertensive nephropathy
Description	RATIONALE: Hypertension can lead to podocyte damage and subsequent apoptosis, eventually resulting in glomerulosclerosis. Although alleviating podocyte apoptosis has clinical significance for the treatment of hypertensive nephropathy, an effective therapeutic target has not yet been identified. The function of Septin4, a pro-apoptotic protein and an important marker of organ damage, is regulated by post-translational modification (PTM). However, the exact role of Septin4 in regulating podocyte apoptosis and its connection to hypertensive renal damage remains unclear. OBJECTIVE: We investigated the function and underlying mechanism of Septin4 in AngII-induced hypertensive nephropathy to discover a theoretical basis for targeted treatment. METHODS AND RESULTS: Using transgenic Septin4-K174Q mutant mice treated with the antioxidant Tempol, we found that hyperacetylation of the K174 site of Septin4 exacerbates AngII induced hypertensive renal injury resulting from oxidative stress. Proteomics and western blotting assays indicated that Septin4-K174Q activates the cleaved-PARP1-cleaved-Caspase3 pathway. In Septin4-knockdown human renal podocytes, Septin4-K174R, which mimics deacetylation at K174, rescues podocyte apoptosis induced by AngII. We conclude that Septin4, when activated through acetylation of K174 (K174Q), promotes hypertensive renal injury. Immunoprecipitation and mass spectrometry analyses identified SIRT2 as a deacetylase that interacts with the Septin4 GTPase domain and deacetylates Septin4-K174. In Sirt2-deficient mice and SIRT2-knockdown renal podocytes, Septin4-K174 remains hyperacetylated and exacerbates hypertensive renal injury. By contrast, in Rosa26-Sirt2-Flag (SIRT2-TG) mice and SIRT2-knockdown renal podocytes re-expressing wild-type SIRT2, Septin4-K174 is hypoacetylated and mitigates hypertensive renal injury. CONCLUSION: Septin4-K174R, which mimics deacetylation by SIRT2, inhibits the cleaved-PARP1-cleaved-Caspase3 pathway. Septin4-K174R acts as a renal protective factor, mitigating AngII-induced hypertensive renal injury. These findings indicate that Septin4-K174 is a potential therapeutic target for the treatment of hypertensive renal injury.
HostingRepository	iProX
AnnounceDate	2022-12-05
AnnouncementXML	Submission_2023-03-05_19:59:40.399.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Ying Zhang
SpeciesList	scientific name: Mus musculus; NCBI TaxID: 10090;
ModificationList	acetylated residue
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2022-12-04 23:11:13	ID requested
1	2022-12-04 23:11:25	announced
⏵ 2	2023-03-05 19:59:41	announced	2023-03-06: Update publication information.

Zhang Y, Zhang N, Zou Y, Song C, Cao K, Wu B, You S, Lu S, Wang D, Xu J, Huang X, Zhang P, Fan Z, Liu J, Cheng Z, Zhang Z, Kong C, Cao L, Sun Y, Deacetylation of Septin4 by SIRT2 (Silent Mating Type Information Regulation 2 Homolog-2) Mitigates Damaging of Hypertensive Nephropathy. Circ Res, 132(5):601-624(2023) [pubmed]

submitter keyword: SIRT2, Septin4, Deacetylation, Hypertensive nephropathy

Ying Zhang
contact affiliation	The First Hospital of China Medical University
contact email	yzhang02@cmu.edu.cn
lab head
Ying Zhang
contact affiliation	The First Hospital of China Medical University
contact email	yzhang02@cmu.edu.cn
dataset submitter

iProX dataset URI