PXD047442-2

PXD047442 is an original dataset announced via ProteomeXchange.

Title	Selective hypoxia-sensitive oxomer formation by FIH prevents binding of the NF-kB inhibitor IkBß to NF-?B subunits
Description	Pharmacologic inhibitors of cellular hydroxylase oxygen sensors are protective in multiple pre-clinical in vivo models of inflammation. However, the molecular mechanisms underlying this regulation are only partly understood, preventing clinical translation. We previously proposed a new mechanism for cellular oxygen sensing: oxygen-dependent, (likely) covalent protein oligomer (oxomer) formation. Here, we report that the cellular oxygen sensor factor inhibiting HIF (FIH) forms an oxomer with the NF-?B inhibitor ß (I?Bß). The formation of this protein complex required FIH enzymatic activity and was prevented by pharmacologic inhibitors. Oxomer formation was highly hypoxia-sensitive and very stable. No other member of the I?B protein family formed an oxomer with FIH, demonstrating that FIH-I?Bß oxomer formation was highly selective. In contrast to FIH-dependent oxomer formation with the deubiquitinase OTUB1, FIH-I?Bß oxomer formation did not occur via an I?Bß asparagine residue, but through the amino acid sequence VAERR contained within a loop between I?Bß ankyrin repeat domains 2 and 3. Oxomer formation prevented I?Bß from binding to its primary interaction partners p65 and c-Rel, subunits of NF-?B, the master regulator of the cellular transcriptional response to pro-inflammatory stimuli. We therefore propose that FIH-mediated oxomer formation with I?Bß contributes to the hypoxia-dependent regulation of inflammation.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:45:44.110.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Alex von Kriegsheim
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-12-01 04:59:40	ID requested
1	2024-06-16 01:17:13	announced
⏵ 2	2024-10-22 06:45:48	announced	2024-10-22: Updated project metadata.

10.1080/10985549.2024.2338727;

Volkova YL, Jucht AE, Oechsler N, Krishnankutty R, von Kriegsheim A, Wenger RH, Scholz CC, B Subunits. Mol Cell Biol, 44(4):138-148(2024) [pubmed]

submitter keyword: HIF1AN

HIF

hydroxylase inhibitor

inflammation

oxygen sensor

Carsten Scholz
contact affiliation	uni-greifswald
contact email	Carsten.Scholz@med.uni-greifswald.de
lab head
Alex von Kriegsheim
contact affiliation	University of Edinburgh
contact email	alex.vonkriegsheim@ed.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD047442
     1. Label: PRIDE project
     2. Name: Selective hypoxia-sensitive oxomer formation by FIH prevents binding of the NF-kB inhibitor IkBß to NF-?B subunits