USP3 plays a critical role in the induction of innate immune tolerance.
NF-κB signaling
inflammatory response
innate immune memory
toll-like receptors
ubiquitination
Journal
EMBO reports
ISSN: 1469-3178
Titre abrégé: EMBO Rep
Pays: England
ID NLM: 100963049
Informations de publication
Date de publication:
06 Dec 2023
06 Dec 2023
Historique:
revised:
25
10
2023
received:
14
07
2023
accepted:
26
10
2023
medline:
11
12
2023
pubmed:
17
11
2023
entrez:
16
11
2023
Statut:
ppublish
Résumé
Microbial products, such as lipopolysaccharide (LPS), can elicit efficient innate immune responses against invading pathogens. However, priming with LPS can induce a form of innate immune memory, termed innate immune "tolerance", which blunts subsequent NF-κB signaling. Although epigenetic and transcriptional reprogramming has been shown to play a role in innate immune memory, the involvement of post-translational regulation remains unclear. Here, we report that ubiquitin-specific protease 3 (USP3) participates in establishing "tolerance" innate immune memory through non-transcriptional feedback. Upon NF-κB signaling activation, USP3 is stabilized and exits the nucleus. The cytoplasmic USP3 specifically removes the K63-linked polyubiquitin chains on MyD88, thus negatively regulating TLR/IL1β-induced inflammatory signaling activation. Importantly, cytoplasmic translocation is a prerequisite step for USP3 to deubiquitinate MyD88. Additionally, LPS priming could induce cytoplasmic retention and faster and stronger cytoplasmic translocation of USP3, enabling it to quickly shut down NF-κB signaling upon the second LPS challenge. This work identifies a previously unrecognized post-translational feedback loop in the MyD88-USP3 axis, which is critical for inducing normal "tolerance" innate immune memory.
Identifiants
pubmed: 37971847
doi: 10.15252/embr.202357828
pmc: PMC10702844
doi:
Substances chimiques
NF-kappa B
0
Myeloid Differentiation Factor 88
0
Lipopolysaccharides
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e57828Subventions
Organisme : NCI NIH HHS
ID : R01 CA246547
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA101795
Pays : United States
Informations de copyright
© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
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