PXD066206

PXD066206 is an original dataset announced via ProteomeXchange.

Title	Cardiovirus-Mediated PKR Inhibition Results from Nucleocytoplasmic Trafficking Disruption
Description	Protein kinase R (PKR) is a key antiviral kinase activated by binding double-stranded RNA (dsRNA) produced during viral replication. Upon activation, PKR phosphorylates eIF2α, leading to the inhibition of translation and viral replication. However, many viruses have evolved mechanisms to counteract PKR activity. In Cardioviruses, the Leader protein (L), a short peptide cleaved from the N-terminus of the viral polyprotein, not only inhibits PKR but also blocks interferon production and disrupts nucleocytoplasmic trafficking (NCT). L disrupts NCT by recruiting host RSK kinases to the nuclear pore complex (NPC), where RSK phosphorylates FG-nucleoporins, thereby impairing NCT. L mutations that affect NCT disruption also impact its ability to inhibit PKR, suggesting a mechanistic link. Recombinant TMEV and EMCV viruses designed to disrupt NCT through different mechanisms exhibited some extent of PKR inhibition, supporting the link between NCT disruption and PKR inhibition. Immunostaining and live-cell imaging revealed that L-induced NCT disruption redistributes a fraction of PKR to the nucleoli, where PKR remains inactive. This suggests that nucleolar sequestration contributes to PKR inhibition. Additionally, L-mediated NCT disruption leads to the release of nuclear RNA-binding proteins (nRBPs) into the cytosol, which may bind or modify viral dsRNA, further preventing PKR activation. Collectively, these results highlight nucleocytoplasmic trafficking as a critical regulatory mechanism governing PKR activation. Thus, beyond the specific action of the Cardiovirus L protein, our study reveals a broader principle in which interference with host nucleocytoplasmic transport can significantly impact the subcellular localization and functional regulation of immune effectors, such as PKR
HostingRepository	PRIDE
AnnounceDate	2025-11-17
AnnouncementXML	Submission_2025-11-17_01:26:17.621.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD066206
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Didier Vertommen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2025-07-16 04:34:20	ID requested
⏵ 1	2025-11-17 01:26:18	announced

10.6019/PXD066206;

submitter keyword: nucleocytoplasmic traffic,PKR, nucleocytoplasmic trafficking disorder (NCTD), cardiovirus, stress granules., picornavirus, nucleoli, double-stranded RNA, EIF2AK2

Thomas Michiels
contact affiliation	Université catholique de Louvain, de Duve Institute, 74 avenue Hippocrate (VIRO-B1.74.07), B-1200 Brussels, Belgium
contact email	thomas.michiels@uclouvain.be
lab head
Didier Vertommen
contact affiliation	UCL - de Duve Institute, Brussels Belgium
contact email	didier.vertommen@uclouvain.be
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD066206
     1. Label: PRIDE project
     2. Name: Cardiovirus-Mediated PKR Inhibition Results from Nucleocytoplasmic Trafficking Disruption