PXD058618

PXD058618 is an original dataset announced via ProteomeXchange.

Title	USP18 interactor and PTM mass spectrometry
Description	The ubiquitin-like protein ISG15 is activated in response to type 1 interferons and its conjugation to proteins regulates the response to bacterial and viral infection. Its subsequent deconjugation, by a single human enzyme, USP18, critically controls interferon signaling and the defense against pathogens. Accordingly, human mutations in USP18 give rise to interferonopathies. However, the molecular determinants underlying USP18 specificity for ISG15 remain elusive. We have identified key mechanisms that underlie the specificity of USP18 towards ISG15, by taking advantage of USP18’s largely unstudied human paralog USP41. Remarkably, we show that USP41 completely lacks the ability to perform deISGylation, despite possessing a catalytic domain that is 97% identical to that of USP18. Using a variety of in vitro and in vivo assays, we performed a comparative analysis to reveal new mechanisms of deISGylation. We define a short, conserved stretch of amino acids, that we term the TAIL motif, as well as a conserved leucine residue in the catalytic domain, which are necessary for deISGylation. Structural analysis revealed that these residues contact ISG15 and are conserved between USP18 and PLpro from SARS-Cov2, underlining their importance in ISG15 specification. Finally, while little is known about USP41, we found that it can bind and negatively regulate FAT10, a poorly studied Ubl which is also involved in the interferon response. While a FAT10 deconjugating enzyme has long been postulated, no such enzyme has ever been described.
HostingRepository	PRIDE
AnnounceDate	2025-07-14
AnnouncementXML	Submission_2025-07-13_16:06:22.549.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Michael Emanuele
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2024-12-05 09:14:25	ID requested
⏵ 1	2025-07-13 16:06:23	announced

10.1016/j.jbc.2025.110288;

Bonacci T, Bolhuis DL, Brown NG, Emanuele MJ, Mechanisms of USP18 specificity toward ISG15 revealed by paralog sequence analysis comparison. J Biol Chem, 301(7):110288(2025) [pubmed]

submitter keyword: USP41, ISG15, deISGylation, Deubiquitinase,USP18

Michael J Emanuele
contact affiliation	University of North Carolina at Chapel Hill Dept of Pharmacology Lineberger Comprehenisve Cancer Center
contact email	emanuele@email.unc.edu
lab head
Michael Emanuele
contact affiliation	UNC Chapel Hill
contact email	emanuele@email.unc.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD058618
     1. Label: PRIDE project
     2. Name: USP18 interactor and PTM mass spectrometry