# Interdependence of Antimicrobial and Pro-inflammatory Activities Mediated by S100A12 in the Innate Immune Response

> **NIH NIH R15** · COLLEGE OF STATEN ISLAND · 2022 · $471,269

## Abstract

Sequestration of critical nutrients (such as Zn(II), Fe(II) and Mn(II)) during pathogenic invasion is a
common strategy undertaken by host cells to thwart infection. In humans, this task is performed by a subset of
Ca(II) binding S100 proteins such as S100A12. By chelating Zn(II) at its dimeric interface, S100A12 performs
antimicrobial activities. During infection, S100A12 interacts with membrane receptors such as the receptor for
advanced glycation end products (RAGE) to initiate a pro-inflammatory signaling cascade. Although known to
participate in both antimicrobial and pro-inflammatory activities, the mode of interaction of S100A12 with
membrane receptors that initiates inflammatory signaling, is not known. Our research program envisions
investigating molecular-level interactions of S100A12 that instigate inflammatory pathways.
 Our recently reported studies have identified several key features of S100A12 such as (i) the ability of the
protein to form reversible oligomeric assemblies that is mostly dominated by Zn(II) binding; (ii) Zn(II) ligation
introduced conformational changes to functionally relevant domains of the protein and; (iii) the modulation of
Zn(II) sequestration by Ca(II) at physiologically relevant pH conditions. These results, along with previously
reported studies in the literature demonstrating the presence of oligomeric S100A12 at inflammatory sites in
vivo have laid the foundation of our hypothesis which proposes a metal binding mediated crosstalk between
antimicrobial and inflammatory functions of S100A12. Our research program will undertake a biophysical
approach to investigate molecular level interactions of S100A12 that afford its functions in the immune response.
Focusing on divalent metal ion (Ca(II) and Zn(II)) binding and their influence on S100A12 functions, we propose
the following specific aims to test our hypothesis: (i) calcium induced regulation of structure, dynamics and
functions; (ii) divalent metal ion mediated signal transduction by S100A12; and (iii) molecular basis of S100A12
interactions in inflammatory responses.
 These proposed studies will focus on the role of Ca(II) and Zn(II) binding to atomic- and molecular-level
details to evaluate the factors influencing S100A12-membrane sensor interactions in vitro. The findings of our
work are expected to provide a framework for overall functioning of similar immune system components,
allowing for the development of a generalized model of the immune response. Lastly, this work is also expected
to generate information that could help develop efficient therapeutic targeting molecules such as S100A12 during
aberrant inflammation.

## Key facts

- **NIH application ID:** 10438080
- **Project number:** 2R15GM131338-02
- **Recipient organization:** COLLEGE OF STATEN ISLAND
- **Principal Investigator:** Rupal Gupta
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $471,269
- **Award type:** 2
- **Project period:** 2019-08-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10438080

## Citation

> US National Institutes of Health, RePORTER application 10438080, Interdependence of Antimicrobial and Pro-inflammatory Activities Mediated by S100A12 in the Innate Immune Response (2R15GM131338-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10438080. Licensed CC0.

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