PXD062474

PXD062474 is an original dataset announced via ProteomeXchange.

Title	Acidosis attenuates the hypoxic stabilization of HIF-1α by activating its lysosomal degradation
Description	The adaptive responses to oxygen depletion orchestrated by hypoxia-inducible factors (HIFs) produce profound effects on multiple pathways. A canonical metabolic response is enhanced fermentation, but this can generate an unfavorably acidic environment under poor capillary perfusion. It is unclear how cells balance the metabolic benefits of hypoxic responses against knock-on consequences on acid-base homeostasis. We studied the interplay between hypoxia and acidosis on HIF signaling in colorectal cancer cell lines that can survive acidic conditions. Hypoxia stabilized HIF-1α, but this effect was transient in combination with acidosis. By 48 h, HIF-1α induction decreased in proportion to acidification. Proteomic analyses identified responses that followed HIF-1α, including canonical HIF targets (CA9, PDK1), but these did not reflect a proteome-wide downregulation. Responses to acidosis and hypoxia were enriched in lysosomal proteins, but not proteasomal components, implicating the former degradation pathway in transient HIF-1α activation under acidosis. Moreover, HIF-1α decay was not due to decreased HIF1A transcription but was blocked by lysosomal inactivation (bafilomycin-A1). Acidotic hypoxia increased the abundance of lysosomes and activated autophagy by disabling the inhibitory influence of mammalian target of rapamycin complex 1, resulting in HIF-1α degradation. By blocking HIF-driven fermentative upregulation, this mechanism protects the cellular environment from deleterious acid-overloading, an outcome that outweighs the biosynthetic benefits of raised glycolytic flux under suppressed respiration. Thus, alkaline conditions are permissive for at least some aspects of HIF-1α signaling, but may not reflect tumor microenvironment chemistry. Consequently, acidic hypoxic tumor regions may not necessarily overlay with sites of HIF induction
HostingRepository	PRIDE
AnnounceDate	2025-06-30
AnnouncementXML	Submission_2025-06-29_16:22:33.370.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Sarah Flannery
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Astral

Revision	Datetime	Status	ChangeLog Entry
0	2025-04-01 11:06:55	ID requested
⏵ 1	2025-06-29 16:22:34	announced

10.1083/jcb.202409103;

White B, Wang Z, Dean M, Michl J, Nieora N, Flannery S, Vendrell I, Fischer R, Hulikova A, Swietach P, by activating lysosomal degradation. J Cell Biol, 224(8):(2025) [pubmed]

submitter keyword: acidosis, Colorectal Cancer,Hypoxia inducible factor, hypoxia, tumour microenvironment, SW1222

Iolanda Vendrell
contact affiliation	Target Discovery Institute, Nuffield Dept Medicine, University of Oxford, UK
contact email	iolanda.vendrell@ndm.ox.ac.uk
lab head
Sarah Flannery
contact affiliation	Nuffield Dept Medicine
contact email	sarah.flannery@ndm.ox.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD062474
     1. Label: PRIDE project
     2. Name: Acidosis attenuates the hypoxic stabilization of HIF-1α by activating its lysosomal degradation