# Function of Desmoglein 1/Pemphigus Foliaceus Antigen

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $488,726

## Abstract

The multi-layered epidermis provides an essential barrier against water loss, physical insults, and infection. Its
proper function requires that architectural features be polarized along its entire apical to basal axis. Contributing
to the inherent tissue polarity of the epidermis are seven desmosomal cadherins, intercellular adhesion
molecules that provide mechanical integrity to tissues by anchoring intermediate filaments to the plasma
membrane. Of these, desmoglein 1 (Dsg1) appeared late in evolution along with expansion of epidermal
functions to meet the challenges of life on land. We showed that Dsg1, which is first expressed as cells commit
to differentiate and transit into the suprabasal layers, acts as a scaffold that engages the actin cytoskeleton and
signaling mediators necessary for tissue morphogenesis and terminal differentiation. To achieve these functions
Dsg1 must be properly routed by intracellular trafficking machinery to its final address at the plasma membrane.
Its failure to accumulate on the plasma membrane disrupts organismal homeostasis in patients with the systemic
inflammatory disorder, Severe dermatitis, Allergies and Metabolic wasting (SAM) syndrome, a syndrome we
helped identify. We identified two critical elements of the trafficking machinery required for Dsg1 function-- a
specific dynein microtubule motor complex and an endosomal sorting complex called the retromer, best known
to be involved in neurodegenerative
the
amount,
disorders. that in keratinocytes committing to differentiate,
 retromer/dynein machinery ensures Dsg1 gets to the right plasma membrane “address” and in the right
to mediate a switch from EGFR signaling to actin remodeling
We hypothesize
that drives changes in cell mechanics and
signaling necessary for morphogenesis and immune regulation. We will use optical imaging, biochemistry, and
genetic interference in human 2D and 3D organotypic cultures, human patient materials, and knockout mouse
models to: 1) Define how the retromer and dynein trafficking machinery ensures Dsg1's functional placement on
the plasma membrane necessary to promote the epithelial basal to suprabasal transition, and evaluate the utility
of retromer chaperones as a therapeutic strategy to enhance epidermal stratification and differentiation in vitro
and in vivo; 2) Determine how Dsg1 coordinates a switch from EGFR signaling to actin remodeling by engaging
the actin nucleation promoting factors N-WASP and Arp2/3 to drive cell mechanics necessary for stratification in
vitro and in vivo; and 3) Address the extent to which Dsg1 governs redistribution of actin remodeling factors to
control epidermal immune regulation and expression of IL-23, a pro-inflammatory cytokine that increases in SAM
syndrome caused by loss of Dsg1 function. These studies will establish how Dsg1 coordinates rearrangements
of the cytoskeleton with the biochemical program of differentiation while keeping inflammatory cytokines in check.
Understanding how Dsg1 ...

## Key facts

- **NIH application ID:** 10908443
- **Project number:** 5R01AR041836-32
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Kathleen Janee Green
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $488,726
- **Award type:** 5
- **Project period:** 1993-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10908443

## Citation

> US National Institutes of Health, RePORTER application 10908443, Function of Desmoglein 1/Pemphigus Foliaceus Antigen (5R01AR041836-32). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10908443. Licensed CC0.

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