Abstract
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.
Original language | English (US) |
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Article number | e57828 |
Journal | EMBO Reports |
Volume | 24 |
Issue number | 12 |
DOIs | |
State | Published - Dec 6 2023 |
Keywords
- NF-κB signaling
- inflammatory response
- innate immune memory
- toll-like receptors
- ubiquitination
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Genetics