PXD061276-1

PXD061276 is an original dataset announced via ProteomeXchange.

Title	SUMO operates from a unique long tandem repeat to keep innate immunity in check
Description	The SUMO pathway mainly functions to repress innate immunity in myeloid cells. Inactivating sumoylation triggers a strong, noncanonical, type I interferon (IFN1) response, amplified and coupled with inflammation upon stimulation. These findings transposed to pre-clinical models with the demonstration that sumoylation inhibitors activate antitumor immunity in an IFN1-dependent manner. Yet, how sumoylation represses immune signaling remains largely unknown. Here, we identified MORC3, a negative regulator of IFNB1, as the top SUMO2/3 substrate in myeloid cells. We show that, in monocytes, SUMO functions to repress basal IFNB1 in cis through a single long tandem repeat regulated by MORC3 [MORC3-regulated element (MRE)] that concentrates multiple motifs for the myeloid-enriched PU.1 factor. Inhibiting sumoylation induces a 3D genome reorganization nucleated from the MRE, which acquires both insulator and PU.1-activated enhancer activities, together with loss of H3.3 and H3K9me3 repressive marks and recruitment of PU.1. Paradoxically, MORC3, that interacts with PU.1, is massively recruited, yet unable to repress the MRE. Finally, we show that both sumoylation and MORC3 ATPase cycle are critical for MORC3 repressive activity. Our study thus uncovers an unconventional mechanism in which sumoylation, in concert with MORC3, orchestrates a metastable H3.3/H3K9me3 heterochromatin state on a multi-PU.1 binding platform to prevent an uncontrolled myeloid-specific immune response.
HostingRepository	PRIDE
AnnounceDate	2025-08-16
AnnouncementXML	Submission_2025-08-16_04:28:19.786.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Ivo Hendriks
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	sumoylated lysine
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2025-02-27 09:52:49	ID requested
⏵ 1	2025-08-16 04:28:20	announced

Goffeney A, Hendriks IA, Morel V, Loe-Mie Y, Charon F, Nielsen ML, Cossec JC, Noordermeer D, Seeler JS, Dejean A, SUMO operates from a unique long tandem repeat to keep innate immunity in check. Nucleic Acids Res, 53(14):(2025) [pubmed]

10.1093/nar/gkaf750;

submitter keyword: SUMO, SUMOylation, H3.3, IFN1, H3K9me3, MORC3

Ivo Hendriks
contact affiliation	Proteomics program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
contact email	ivo.a.hendriks@gmail.com
lab head
Ivo Hendriks
contact affiliation	Proteomics program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
contact email	ivo.a.hendriks@gmail.com
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/08/PXD061276

PRIDE project URI

• PRIDE
  1. PXD061276
     1. Label: PRIDE project
     2. Name: SUMO operates from a unique long tandem repeat to keep innate immunity in check