# Role of Stx11 and STXBP2 in lytic granule exocytosis in health and disease

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2020 · $394,911

## Abstract

ABSTRACT
Primary immune deficiencies with impaired cell-mediated cytotoxicity commonly manifest as Familial
Hemophagocytic Lymphohysticytosis (FHL), a life threatening disorder. FHL is characterized by
disproportioned immune response mediated by excessively activated Cytotoxic T-lymphocyte (CTLs), Natural
Killer (NK) and macrophages. FHL subjects usually harbor biallelic germline-mutations in genes involved in
intracellular membrane trafficking including Syntaxin 11 (STX11, FHL-4) and Syntaxin-Binding Protein 2
(STXBP2, FHL-5). Nonetheless, monoallelic mutations have also been associated in FHL, but their clinical and
biological significance remain unclear. Despite evidences linking STX11 and STXBP2 mutations to abnormal
CTL and NK cell activity in FHL patients, there is a significant gap in knowledge about the normal function of
these proteins and how these mutations impact on cytotoxic activity and ultimately lead to disease. This
proposal aims to bridge this gap in knowledge between the genetic findings and the clinical manifestations in
FHL-patients by establishing the basic mechanisms through which STX11/STXBP2 cooperate to effect LG
exocytosis and by dissecting how they are affected in patient cells. STX11 and STXBP2 physically interact in
as yet poorly characterized ways to control the release of lytic granule (LG) content at the immunological
synapse. Data from our lab provide evidences that STX11 also interact with different sets of membrane fusion
proteins that could mediate distinct trafficking steps. We hypothesize that STX11/STXBP2 control endosome-
lysosome trafficking and LG fusion at the plasma membrane through these interactions. We further
hypothesize that FHL mutations interfere with these interactions and thus impair cell-mediated cytotoxicity
and/or survival signaling, a process that ultimately results in an array of immunological disorders with HLH
symptoms. First, we will evaluate how FHL-mutations in STX11 and STXBP2 affect the physical relationship
with one another and with other interacting proteins involved in exocytic and endo-lysosomal pathways by
using biochemical and Mass Spec approaches in patient cells. We will establish how mutations affect the
structural requirements for protein-protein interactions by performing pull-down, liposome co-flotation assays
and surface plasmon resonance experiments. Second, we will assess the biological significance of both
monollelic and biallelic FHL-mutations by investigating the intracellular trafficking defects in FHL-patient cells
using super resolution STED and TIRF microscopy. Moreover, we will establish the molecular mechanisms of
action of these mutations by using a unique in-vitro fusion assay develop in our lab. In summary, our studies
will contribute more broadly to our understanding of the membrane trafficking steps that control cell killing
pathways in CTL and NK cells, help in therapeutic decisions for patients carrying monoallelic mutations,
establish common and gene...

## Key facts

- **NIH application ID:** 9854879
- **Project number:** 5R01AI123538-04
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Claudio Guillermo Giraudo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $394,911
- **Award type:** 5
- **Project period:** 2017-01-25 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9854879

## Citation

> US National Institutes of Health, RePORTER application 9854879, Role of Stx11 and STXBP2 in lytic granule exocytosis in health and disease (5R01AI123538-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9854879. Licensed CC0.

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