# TULP3 integrates essential ciliary functions

> **NIH NIH K99** · STANFORD UNIVERSITY · 2024 · $125,000

## Abstract

PROJECT SUMMARY
Primary cilia play a pivotal role in human health, acting as signaling hubs to sense extracellular cues such as
odorants, metabolites, light, neurotransmitters, and more. Defects or failure of these signaling hubs to function
leads to developmental disorders, immune dysfunction, diabetes, obesity, Parkinson’s disease, cancer, and other
pathologies. An early focus of this grant is the generation of better tools to dissect primary cilia function and
mechanism, such as a protocol for synchronized ciliogenesis in human retinal pigemented epithelial (RPE) cells
coupled with microscopy and shotgun/phosphoproteomic mass spectrometry, to dissect signaling events
temporally and spatially. While mapping ciliogenesis via immunofluorescence with known markers of the stages,
one protein that emerged as a strong candidate for regulating interpathway communication was TULP3, a 50kDa
ciliary protein whose primary known function is in driving the import of ciliary GPCRs through unclear
mechanisms. A combination of synchronization and classical cell biological approaches were used to uncover
novel phenotypes revealing temporal and spatial timing of TULP3’s function in GPCR traffic as well as new
functions in ciliogenesis, downstream of TTBK2 recruitment but before axoneme protrusion. Patient mutations
were identified from the use of GWAS databases to probe for links between protein function and human health.
Constitutive expression of these TULP3 mutants in TULP3 KO background generated new tools to perturb select
functions for TULP3, which is especially powerful for probing function-specific binding domains and partners.
This proposal tests the following hypotheses: TULP3 (i) regulates receptor traffic prior to cargo arrival at the
basal body and coupling to IFT machinery to mediate receptor entry into cilia and (ii) licenses axonemogenesis.
Furthermore, primary cilia perform two different functions in lymphoid tissues: regulating fate change of
hematopoietic stem cells into lymphocytes in the bone marrow, and in the lymph node facilitating lymphocyte
maturation. These hypotheses will be tested in the following aims: Aim 1- Determine the mechanism by which
TULP3 mediates membrane receptor transport into cilia. Aim 2- Identify the function and mechanism of TULP3
in ciliogenesis. Aim 3- Uncover the function of primary cilia and TULP3 in the generation of white blood cells.
These aims will be addressed using cell culture and mouse model systems to probe TULP3 function and its role
in immunity in both in vitro and in vivo contexts. The success of any and all of these aims will provide novel
insight into key mechanisms driving ciliary function and reveal cellular contexts for how disrupted immune
function arises. The study of primary cilia in the lymphatic system is largely uncharted territory. As a result, these
studies are expected to open new fields of investigation into mechanisms of immune regulation.

## Key facts

- **NIH application ID:** 10866216
- **Project number:** 1K99GM154060-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Rachel Elizabeth Turn
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $125,000
- **Award type:** 1
- **Project period:** 2024-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10866216

## Citation

> US National Institutes of Health, RePORTER application 10866216, TULP3 integrates essential ciliary functions (1K99GM154060-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10866216. Licensed CC0.

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