# Role of Protein Ubiquitination in Sepsis

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2020 · $331,582

## Abstract

Project Summary
Sepsis with its complications is a major challenge in contemporary medicine. Approximately 250,000 cases of
sepsis lead to fatalities in the USA annually at huge costs for the healthcare system. Depending on the
standards of medical care, the worldwide mortality rates in septic humans range from 30% to 70% with an
aggregate mortality rate of ~50%. NLRP3 is a key component of the macromolecular signaling complex called
the inflammasome that promotes caspase 1-dependent production of IL-1β pro-inflammatory cytokine involved
in the development of sepsis. Although the factors leading to NLRP3 inflammasome activation have been
extensively studied, the mechanisms for negatively regulating the activation of the NLRP3 inflammasome, and
thus, controlling sepsis, are not known. We found that NLRP3 is inhibited by ubiquitination by Cbl-b, an E3
ubiquitin ligase. The significance of this finding is demonstrated by the observation that that lipopolysaccharide
(LPS) injection or cecal ligation and puncture (CLP) induces a significant mortality in Cblb-/- mice compared to
wild-type (WT) controls, and this increased mortality in Cblb-/- mice induced by LPS is blocked by an IL-1
receptor antagonist or by introducing NLRP3 deficiency. Therefore, our central hypothesis is that during sepsis,
Cbl-b is autoubiquitinated/activated and ubiquitinates NLRP3, which in turn inhibits NLRP3 and attenuates
NLRP3-mediated innate responses. We propose to determine 1) how Cbl-b regulates NLRP3 inflammasome
activation; 2) whether and how Cbl-b controls non-canonical NLRP3 inflammasome in vivo using CLP-induced
sepsis and LPS-induced septic shock as the study models. Understanding the role of Cbl-b in regulating the
NLRP3 inflammasome-mediated signaling pathway will provide novel insights and therapeutic strategies to
combat sepsis.

## Key facts

- **NIH application ID:** 9934097
- **Project number:** 5R01AI121196-06
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** JIAN ZHANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $331,582
- **Award type:** 5
- **Project period:** 2017-11-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934097

## Citation

> US National Institutes of Health, RePORTER application 9934097, Role of Protein Ubiquitination in Sepsis (5R01AI121196-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9934097. Licensed CC0.

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