Related Experiment Video
Updated: Oct 31, 2025
A Mouse Model to Assess Innate Immune Response to Staphylococcus aureus Infection
Published on: February 28, 2019
Neddylation Alleviates Methicillin-Resistant Staphylococcus aureus Infection by Inducing Macrophage Reactive Oxygen
Huiqing Xiu1, Yanmei Peng2, Xiaofang Huang1
1Department of Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Abstract:
Neddylation, a posttranslational modification in which NEDD8 is covalently attached to target proteins, has emerged as an endogenous regulator of innate immunity. However, the role of neddylation in methicillin-resistant Staphylococcus aureus (MRSA) infection remains unknown. In this study, we found that neddylation was activated after MRSA infection in vivo and in vitro. Inhibition of neddylation with MLN4924 promoted injury of liver and kidneys in C57BL/6 mice with MRSA bloodstream infection and increased mortality. Blockade of neddylation, either pharmacologically (MLN4924, DI591) or through the use of Uba3 small interfering RNA, inhibited Cullin3 neddylation and promoted Nrf2 accumulation, thus reducing reactive oxygen species (ROS) induction and bacterial killing ability in mouse peritoneal macrophages. In summary, our findings suggest that activation of neddylation in macrophages plays a critical protective role against MRSA infection by increasing ROS production, partially by signaling through the NEDD8-Cullin3-Nrf2-ROS axis. Furthermore, our results may provide a new non-antibiotic treatment strategy for MRSA infection through targeting of neddylation.
Insights
Neddylation, a key immune process, protects against MRSA infection by boosting reactive oxygen species (ROS). Targeting neddylation offers a potential non-antibiotic strategy for Staphylococcus aureus infections.
Area of Science:
- Immunology
- Molecular Biology
- Microbiology
Background:
- Neddylation, a posttranslational modification, regulates innate immunity.
- The role of neddylation in methicillin-resistant Staphylococcus aureus (MRSA) infection is not understood.
Purpose of the Study:
- To investigate the role of neddylation in MRSA infection.
- To explore neddylation as a potential therapeutic target for MRSA infections.
Main Methods:
- MRSA infection models in vivo and in vitro.
- Pharmacological inhibition of neddylation (MLN4924, DI591).
- Uba3 small interfering RNA (siRNA) to block neddylation.
- Analysis of Cullin3 neddylation, Nrf2 accumulation, and reactive oxygen species (ROS) production in macrophages.
Main Results:
- Neddylation was activated following MRSA infection.
- Inhibition of neddylation increased organ injury and mortality in mice.
- Blocking neddylation reduced ROS production and bacterial killing in macrophages.
- Neddylation blockade led to Nrf2 accumulation via the NEDD8-Cullin3-Nrf2 pathway.
Conclusions:
- Activated neddylation plays a protective role in MRSA infection.
- The NEDD8-Cullin3-Nrf2-ROS axis is crucial for combating MRSA.
- Targeting neddylation presents a promising non-antibiotic therapeutic strategy for MRSA infections.
