# LUBAC-dependent regulation of cell death

> **NIH NIH R01** · SOUTH DAKOTA STATE UNIVERSITY · 2021 · $252,065

## Abstract

PROJECT SUMMARY
Tumor necrosis factor (TNF) is an important cytokine that coordinates cytokine production, inflammation, cell
survival, and cell death. How life and death decisions are made in response to TNF is not completely understood.
Several molecular events determine whether TNF stimulation of cells leads to a transcriptional response that
promotes cell survival or whether it can lead to cell death. Signaling downstream of the TNF receptor is heavily
regulated by post-translation modifications including ubiquitination. LUBAC, a ubiquitin (Ub) E3 ligase consisting
of Sharpin, HOIL and HOIP, is the only Ub ligase described to date that can modify proteins with linear Ub chains
(Met1-Ub chains). LUBAC activity is essential for NF-kB dependent transcription of prosurvival genes upon TNF
stimulation. Cells derived from patients with germline mutations in LUBAC components elicit defective NF-kB-
dependent gene transcription and aberrant activation of cell death pathways. Similarly, murine models with
defective LUBAC components elicit chronic inflammation and increased apoptosis in multiple organs and tissues.
Our published studies indicate that cell death, rather than a deficiency in NF-kB dependent gene transcription,
in LUBAC-deficient (sharpincpdm) animals is driving the TNF-dependent chronic inflammation as this phenotype
is reversed by a compound deficiency in FADD—an important component of the death inducing signaling
complex. This insight led us to the hypothesis that LUBAC activity is directly required for the prevention of cell
death. In aim 1, we will address the molecular basis for LUBAC modification of protein targets with Met1-Ub
chains. We will address how LUBAC can modify FADD with Met1-Ub chains. In aim 2, we will characterize the
functional relevance of FADD modification in cells and use a new Ub-based tool to enrich for Met1-Ub chains. In
aim 3, we will investigate the function of LUBAC auto-ubiquitination and how phosphorylation can regulate
LUBAC’s linear Ub chain forming activity. Our studies will provide mechanistic insight into the etiology of primary
immune deficiencies associated with patients with germline mutations in LUBAC components.

## Key facts

- **NIH application ID:** 10030736
- **Project number:** 1R01GM138861-01
- **Recipient organization:** SOUTH DAKOTA STATE UNIVERSITY
- **Principal Investigator:** Jaime Lopez-Mosqueda
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $252,065
- **Award type:** 1
- **Project period:** 2021-09-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10030736

## Citation

> US National Institutes of Health, RePORTER application 10030736, LUBAC-dependent regulation of cell death (1R01GM138861-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10030736. Licensed CC0.

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