# Mechanisms of Type III protein secretion

> **NIH NIH R37** · YALE UNIVERSITY · 2020 · $629,647

## Abstract

Program Director/Principal Investigator (Last, First, Middle): Galán, Jorge
PROJECT SUMMARY: Many symbiotic or pathogenic bacteria have evolved complex specialized machines known as type
III secretion systems (T3SS), which have the capacity to transfer multiple bacterially-encoded proteins into host
eukaryotic cells. These machines are of great interest because they are central to the pathogenic or symbiotic
relationships of the bacteria that encode them. Proteins delivered by these machines, collectively referred to as
“effectors”, can modulate a great variety of eukaryotic cellular functions to shape the bacteria/host cell functional
interphase. Through work supported by this Grant, we have been studying a T3SS from Salmonella enterica serovar
Typhimurium (S. Typhimurium), encoded within its pathogenicity island 1 (SPI-1). This system mediates several
phenotypes that are essential for virulence including bacterial entry into and survival within non-phagocytic cells, the
induction of programmed cell death in macrophages, and the modulation of innate immune responses and
inflammation in the intestinal tract. The central component of all T3SSs is the needle complex, a supramolecular
structure which allows the translocation of proteins through the bacterial envelope during their journey to eukaryotic
target cells. The needle complex works in association with other components such as the export apparatus, which
mediates passage of the secreted proteins through the bacterial inner membrane, and the “sorting platform”, a
cytoplasmic structure that establishes an order in the secretion process. Additional components regulate the function
of this machine to ensure that it is activated and deployed at the appropriate time (i. e. upon contact with target cells).
Energy to drive protein translocation and the unfolding of the protein substrates is derived from an associated ATPase
as well as a proton gradient established by poorly understood mechanisms. This research project intends to
investigate less understood aspects of type III protein secretion including the mechanisms of sensing, signal
transduction, and activation of the type III secretion machine, the deployment of the T3SS translocon into the target
eukaryotic cell membrane, the structure and function of the T3SS export apparatus, and the mechanisms of by which
the T3SS recognizes its substrates. Accomplishing these objectives will not only enhance our understanding of
Salmonella spp. pathogenesis but also our understanding of T3SSs in general. Since this system is central to the
pathogenesis of many important pathogenic bacteria, these studies may provide the bases for the development of
broadly applicable anti-infective strategies.
RELEVANCE: Many important bacterial pathogens such as Salmonella, Yersinia, Shigella, E. coli, Pseudomonas
aeruginosa, Burkhodleria spp., Chlamydia spp., and Bordetella pertussis possess specialized nanomachine known as
the type III protein secretion system, which is ...

## Key facts

- **NIH application ID:** 9853860
- **Project number:** 4R37AI030492-32
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Jorge E Galan
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $629,647
- **Award type:** 4C
- **Project period:** 1991-01-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9853860

## Citation

> US National Institutes of Health, RePORTER application 9853860, Mechanisms of Type III protein secretion (4R37AI030492-32). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9853860. Licensed CC0.

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