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PXD045912

PXD045912 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleConcerted action of RNase T2 and PLD exonucleases in RNA processing for TLR7 activation
DescriptionToll-like receptor 7 (TLR7) plays a key role in the recognition of RNA viruses and the subsequent induction of an innate immune response. TLR7 contains two ligand binding pockets that recognize distinct RNA degradation products: Pocket 1 recognizes guanosine nucleotides and pocket 2 coordinates short, pyrimidine-rich RNA fragments, while the engagement of both pockets is required to activate TLR7. How these ligands are generated within the endolysosomal compartment is currently unknown. Using a pDC cell line, we here show that the endonuclease RNase T2 and the 5' exonucleases PLD3 and PLD4 act in concert to produce these ligands. On the one hand, RNase T2 generates 2',3'-cyclophosphate-guanosine terminated RNA fragments upon which PLD exonuclease activity acts to release the terminal 2',3'-cyclic GMP. This molecule serves as the physiological ligand for the first binding pocket. On the other hand, PLD activity is also required to generate short RNA fragments that occupy the second binding pocket of TLR7. While PLD3 and PLD4 exert comparable catalytic activities, the almost exclusive expression of PLD4 in pDCs suggests that PLD4 is the relevant exonuclease for pDC activation in the human system. Biochemical and structural studies of PLD3 and PLD4 show that these enzymes form homodimers with two ligand binding sites. Dimer formation is critical for catalytic activity, and previously identified disease-associated mutants fail to form stable dimers. In conclusion, our data provide a mechanistic basis for the recognition of RNA fragments by TLR7.
HostingRepositoryPRIDE
AnnounceDate2024-06-19
AnnouncementXMLSubmission_2024-06-19_02:11:39.003.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterJan Bernd Stöckl
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListiodoacetamide derivatized residue
InstrumentQ Exactive HF
Dataset History
RevisionDatetimeStatusChangeLog Entry
02023-10-05 07:08:39ID requested
12024-06-19 02:11:39announced
Publication List
10.1016/J.IMMUNI.2024.04.010;
Keyword List
submitter keyword: toll-like receptor,Proteomics, nuclease, LC-MS/MS
Contact List
Thomas Fröhlich
contact affiliationLudwig-Maximilians-Universität München Genzentrum Laboratory for Functional Genome Analysis Feodor-Lynen-Str. 25 D-81377 München
contact emailfrohlich@genzentrum.lmu.de
lab head
Jan Bernd Stöckl
contact affiliationGenzentrum der LMU München
contact emailstoeckl@genzentrum.lmu.de
dataset submitter
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