# Regulation of TLR trafficking for proper self versus non-self discrimination

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2021 · $445,067

## Abstract

Regulation of TLR trafficking for proper self versus non-self discrimination
The strategy of sensing nucleic acids by the innate immune system enables broad recognition of pathogens
but exposes the host to the risk of autoimmunity. Recognition of self RNA and DNA by members of the Toll-like
receptor (TLR) family can drive pathology in autoimmune diseases such as lupus. How TLRs are regulated to
permit recognition of pathogens while avoiding self recognition remains a key unanswered question. This
proposal addresses this gap in our understanding by focusing on a critical TLR regulatory protein called
Unc93b1. Previous work by our group and by other groups has shown that Unc93b1 controls the trafficking
and localization of endosomal TLRs. We recently performed a saturating mutagenesis screen of Unc93b1 to
systematically dissect Unc93b1 function, and the results of this screen have transformed our view of
Unc93b1's role in TLR regulation. Our preliminary results support three new concepts: (1) Unc93b1 is a multi-
functional adaptor that has distinct functional domains that specifically regulate individual nucleic acid-sensing
TLRs; (2) Unc93b1 is more than a trafficking chaperone, but appears to be critical for regulation of TLR
signaling itself; (3) Unc93b1 not only positively regulates TLRs, but also appears to play an important role in
negative regulation of TLR signaling. We investigate these concepts over three Aims. Aim 1 seeks to identify
the molecular mechanisms by which Unc93b1 positively regulates trafficking and function of individual TLRs.
Aims 2 and 3 will explore how Unc93b1 negatively regulates TLR7 and TLR3 responses to endogenous RNAs.
Altogether, the work in this proposal will discover new pathways that regulate TLR function and will greatly
improve our understanding of how TLRs balance recognition of microbial versus self nucleic acids.

## Key facts

- **NIH application ID:** 10239031
- **Project number:** 5R01AI072429-14
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Gregory M Barton
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $445,067
- **Award type:** 5
- **Project period:** 2008-02-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10239031

## Citation

> US National Institutes of Health, RePORTER application 10239031, Regulation of TLR trafficking for proper self versus non-self discrimination (5R01AI072429-14). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10239031. Licensed CC0.

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