# Endosomal TLR transport in B cell signaling and autoimmunity

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $193,500

## Abstract

PROJECT SUMMARY
Nucleic acid-sensing (NA)-TLRs, notably TLR7 and TLR9, are central players in the pathogenesis of lupus and
consequently targeting NA-TLR signaling has been shown to have therapeutic efficacy, but a clinically relevant
strategy for specifically inhibiting NA-TLRs has remained elusive. Thus, there is substantial interest in better
understanding their basic biology. NA-TLRs are transported from the endoplasmic reticulum to the
endolysosomal compartment where they engage ligands and provide signals to activate cells and
subsequently the immune system. This project proposes to define the critical endosomal compartments
relevant to NA-TLR signaling, B cell activation, autoAb production, and end organ disease. This is based on
the premise that endosomal transport of NA-TLRs is similar to the intracellular trafficking system utilized for the
biogenesis and function of lysosome-related organelles and that NA-TLRs are a partial form of LROs in NA-
TLR-expressing cells. Deficiency of LRO-forming complexes is associated with a rare recessive disorder,
called the Hermansky-Pudlak syndrome (HPS) composed of several independent genetic and functional
defects that share a common pathway and nearly identical phenotype. This project will use deficiencies in HPS
genes as to identify the stages of LRO biogenesis required for NA-TLR signaling and autoimmunity using
specifically defects in the AP-3 and BLOC-1 to-3 complexes. This will be accomplished by defining the role of
these gene in the development of lupus (aim1), defining the role of AP-3 in TLR signaling in B cells (aim 2),
and defining how these four genes function in B cell TLR transport and signaling (aim 3). This project should
yield new insights into the biology of NA-TLR signaling within the endolysosomal compartments and the
relevance of these compartments to NA-TLR-mediated B cell activation, autoAb production, and systemic
autoimmune disease.

## Key facts

- **NIH application ID:** 9870853
- **Project number:** 5R01AI144070-02
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** DWIGHT H KONO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $193,500
- **Award type:** 5
- **Project period:** 2019-02-12 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9870853

## Citation

> US National Institutes of Health, RePORTER application 9870853, Endosomal TLR transport in B cell signaling and autoimmunity (5R01AI144070-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9870853. Licensed CC0.

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