PXD076447

PXD076447 is an original dataset announced via ProteomeXchange.

Title	The GET Pathway Modulates Azole Susceptibility through Sterol Metabolic Remodeling and Protein Trafficking in Filamentous Fungi
Description	Azole antifungals are widely used to control fungal infection, yet resistance mechanisms beyond drug efflux and target modification remain insufficiently understood. Here, we identified the Guided Entry of Tail-anchored proteins (GET) pathway as a conserved regulator of azole susceptibility in Neurospora crassa and Aspergillus fumigatus. Deletion or dysfunction of the core GET components Get-3 or Get-4 confers resistance to multiple azoles without impairing hyphal growth or sporulation. Mechanistically, GET deficiency neither reduced intracellular accumulation nor altered drug efflux and target expression or total ergosterol levels. Instead, GET-deficient strains displayed significantly reduced accumulation of the toxic sterol intermediate 14α-methyl-3,6-diol under azole stress, indicating a potential bypass of azole-induced sterol toxicity. Proximity labeling and functional validation indicated that GET deficiency perturbs the trafficking of multiple azole-resistance-associated proteins, including the key tail-anchored protein transporter Emp-47 and mitochondrial Cox subunits Cox-4 and Cox-15, which deletion enhanced azole resistance. Transcriptomic and functional analysis further revealed that GET disruption altered the expression of some azole resistance-associated genes, which involve in membrane transport, metabolism, and cell wall organization, independent of canonical stress pathways. In this study, a total of 17 new genes that modulate azole susceptibility were identified. Collectively, our findings uncover a non-classical mechanism of azole resistance mediated by GET-dependent protein trafficking and metabolic adaptation, conserved across filamentous fungi.
HostingRepository	iProX
AnnounceDate	2026-04-01
AnnouncementXML	Submission_2026-04-01_02:03:47.699.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Shuting Ye
SpeciesList	scientific name: Neurospora crassa OR74A; NCBI TaxID: 367110;
ModificationList	No PTMs are included in the dataset
Instrument	TripleTOF 5600

Revision	Datetime	Status	ChangeLog Entry
0	2026-04-01 02:03:16	ID requested
⏵ 1	2026-04-01 02:03:48	announced

Dataset with its publication pending

submitter keyword: GET pathway, azole resistance, TA (tail-anchored) proteins, Get-3, Get-4, Neurospora crassa, Aspergillus fumigatus

Xianyun Sun
contact affiliation	Institute of Microbiology, Chinese Academy of Sciences
contact email	sunxy@im.ac.cn
lab head
Shuting Ye
contact affiliation	Institute of Microbiology, Chinese Academy of Sciences
contact email	1525373150@qq.com
dataset submitter

iProX dataset URI