Cardiomyocyte-enriched OTUD5 deubiquitinates NLRP3, inhibiting inflammasome activation to alleviate septic cardiomyopathy.
Background
Septic cardiomyopathy (SCM) is a critical complication of sepsis, representing the primary cause of mortality in affected patients. Despite its severe impact, the precise mechanisms driving SCM pathogenesis remain largely undefined. Deubiquitinating enzymes (DUBs) are emerging as crucial regulators in various cardiovascular diseases, influencing protein stability and signaling pathways. Understanding their role in SCM could uncover novel therapeutic targets to address the significant unmet medical need in managing this life-threatening condition.
Study Design
Researchers investigated deubiquitinating enzymes in septic myocardial injury using public RNA-Seq data. Pyroptosis was induced in primary neonatal rat cardiomyocytes with lipopolysaccharide (LPS) and nigericin. Levels of IL-1β, Western blot markers, PI staining, CCK-8 viability, and LDH release were assessed. Potential substrates of OTUD5 were identified via Co-immunoprecipitation. Cardiomyocyte-specific OTUD5-knockout mice, generated by CRISPR/Cas9, were subjected to LPS- or Caecal ligation and puncture (CLP)-induced sepsis models to evaluate cardiac function and pyroptosis. AAV9-mediated cardiomyocyte-specific OTUD5 overexpression in NLRP3-knockout mice validated the functional interaction.
Results
The deubiquitinating enzyme OTUD5 was identified as significantly upregulated in myocardial tissue during LPS- and CLP-induced sepsis. Cardiomyocyte-specific knockout of OTUD5 led to exacerbated septic myocardial injury and pyroptosis, indicating its protective role. Mechanistically, OTUD5 directly interacted with NLRP3, with its C224 site being crucial for facilitating NLRP3 deubiquitination. This deubiquitination event directly inhibited NLRP3 activation, a key step in inflammasome assembly and pyroptosis. Importantly, the protective effects observed with OTUD5 overexpression were completely lost in NLRP3 knockout mice, underscoring that OTUD5's function in ameliorating septic cardiomyopathy is dependent on its interaction with NLRP3.
Key Findings
- OTUD5 expression is significantly upregulated in myocardial tissue during sepsis.
- Cardiomyocyte-specific OTUD5 knockout exacerbates septic myocardial injury and pyroptosis.
- OTUD5 directly interacts with NLRP3 via its C224 site to promote NLRP3 deubiquitination.
- OTUD5 inhibits NLRP3 inflammasome activation, thereby suppressing pyroptosis.
- Protective effects of OTUD5 overexpression are lost in NLRP3 knockout mice, confirming NLRP3 dependence.
Why It Matters
OTUD5 emerges as a promising therapeutic target for septic cardiomyopathy, offering a novel mechanism to suppress the detrimental NLRP3 inflammasome pathway. This discovery provides a deeper understanding of SCM pathogenesis, moving beyond symptomatic treatment to target underlying inflammatory drivers. For clinicians and researchers, this opens avenues for developing new interventions that specifically modulate DUB activity or NLRP3 deubiquitination. While preclinical, this work suggests that strategies to enhance cardiomyocyte-specific OTUD5 expression or activity could potentially mitigate cardiac dysfunction and improve outcomes in sepsis patients, warranting further translational research.
septic-cardiomyopathy
sepsis
otud5
nlrp3
inflammasome
pyroptosis