USP3 plays a critical role in the induction of innate immune tolerance
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 16, 2023
- Source ID
- 10.15252/embr.202357828
Entities
People
- Bingnan Yin
- Changsheng Xing
- Chen Qian
- Helen Y. Wang
- Jiayu Ou
- Jun Cui
- Junjun Chu
- Motao Zhu
- Rong-Fu Wang
- Tianhao Duan
- Xin Liu
- Yanchun Feng
- Yang Du
Organizations
- Houston Methodist Hospital
- National Cancer Institute
- National Natural Science Foundation of China
- Sun Yat-sen University
- United States Department of Defense
- University of Southern California