# Molecular regulation of anti-inflammatory cytokine receptor in sepsis

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2021 · $419,248

## Abstract

Abstract
Sepsis is the 10th leading cause of death in the US. An unresolved systemic cytokine storm
caused by bacterial infection is a hallmark of sepsis. The robust acute inflammatory response,
through Toll Like Receptors (TLRs) and interleukin-1R like receptors (ILRs), trigger detrimental
effects including multi-organ failure. Despite extensive research, therapies for sepsis focus on
the use of antimicrobials that lead to multi-drug resistance. Hence, an unmet scientific need is to
understand the molecular regulation of anti-inflammatory responses that diminish the severity of
tissue injury. Single immunoglobulin interleukin-1-related receptor (SIGIRR), which is also
known as Toll/IL-1 receptor 8, exhibits an anti-inflammatory effect against TLRs and ILRs
signaling. Recently, IL-37, which is a suppressor of innate immunity, has been identified as the
SIGIRR ligand. Both IL-37 and SIGIRR have been recognized as major therapeutic targets to
lessen cytokine storm, however, very little is known regarding the molecular regulation of
SIGIRR stability. Receptor degradation, a negative feedback regulation of receptor function, is a
highly regulated process by post-translational modification, such as phosphorylation and
ubiquitination. Ubiquitination is a molecular signal for protein degradation in either the
proteasome or lysosome. De-ubiquitination, which is mediated by deubiquitinating enzymes
(DUBs), tightly controls protein stability by removal of ubiquitin chains from target proteins. In
our preliminary data, we discovered that (i) SIGIRR is poly-ubiquitinated and degraded in the
proteasome in response to its ligand binding; (ii) Ubiquitin-specific protease (USP13), a
member of DUBs, targets and stabilizes SIGIRR by hydrolyzing the ubiquitin chains from
SIGIRR; (iii) glycogen synthase kinase 3β (GSK3β) phosphorylates SIGIRR and interrupts the
association between SIGIRR and USP13, thereby reducing SIGIRR stability; (iv) USP13
increases survival rate in experimental sepsis. These observations have led to the following
hypothesis: USP13 ameliorates cytokine storm and septic shock through deubiquitination and
stabilization of the anti-inflammatory receptor, SIGIRR. To evaluate this hypothesis we will
determine 1) molecular signature of USP13-promoted SIGIRR stability; 2) if GSK3β-induced
disruption of USP13/SIGIRR interaction lessens anti-inflammatory effects of SIGIRR; 3) if
stabilization of SIGIRR by USP13 mitigates endotoxin-induced pro-inflammatory responses. In
summary, this application provides molecular mechanisms by which SIGIRR is degraded via
phosphorylation-driven ubiquitination. Our preliminary data has uncovered two previously
unrecognized post-translational modifications of SIGIRR: phosphorylation and ubiquitination.
Two mediators were revealed: GSK3β, which phosphorylates SIGIRR; and USP13, which de-
ubiquitinates SIGIRR. These studies will be the first to elucidate that phosphorylation of SIGIRR
promotes its ubiquitination by disassoci...

## Key facts

- **NIH application ID:** 10125185
- **Project number:** 5R01HL136294-04
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Yutong Zhao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $419,248
- **Award type:** 5
- **Project period:** 2018-11-10 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10125185

## Citation

> US National Institutes of Health, RePORTER application 10125185, Molecular regulation of anti-inflammatory cytokine receptor in sepsis (5R01HL136294-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10125185. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*