# Dissecting the means by which type 3 substrates are defined & secreted

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $510,186

## Abstract

The virulence of many human bacterial pathogens is dependent on transkingdom nanomachines, including
type III secretion systems (T3SSs), which act to directly deliver tens of virulence proteins, often referred to as
effectors, into the cytosol of mammalian cells. Many critical gaps exist in our understanding of how type III
secreted (T3S) proteins, referred to as effectors, are defined and delivered to the T3S apparatus (T3SA). While
each pathogen injects its own unique set of effectors into hosts, components of their machines share a high
degree of similarity. For several decades, the dogma has been that the effector secretion is dependent on
small acidic T3S chaperones that bind to their N-terminal regions. These chaperones control the hierarchy of
secretion of proteins by mediating their recruitment to the sorting platform, a complex that cycles between the
cytosol and membrane-embedded T3SA. Interestingly, cognate chaperones have not yet been identified for
the majority of T3S effectors, including those from intensively studied Salmonella, Yersinia, Shigella and
pathogenic Escherichia T3SSs. Here, we present data that support the existence of a noncanonical T3SS
chaperone-independent (CI) pathway likely conserved across numerous phylogenetically distinct T3SS
families. Here, using the Shigella flexneri T3SS as a model system, we propose to:
 1. Determine how T3S chaperones are recruited to the sorting platform. Using the Protein Interaction
 2. Dissect the molecular mechanisms by which CI effectors are recognized and delivered to the T3SA.
 3. Investigate the existence of a co-translational ATPase-independent type III secretion pathway.
Together the proposed studies shown not only advance our understanding regarding how T3S effectors are
defined and delivered to the T3SA, but also result in the identification of targets for the development of novel
antimicrobial agents that target the virulence of the large family of Gram-negative bacterial pathogens whose
virulence is dependent on a functional T3SS.

## Key facts

- **NIH application ID:** 9856979
- **Project number:** 5R01AI128360-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** CAMMIE LESSER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $510,186
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856979

## Citation

> US National Institutes of Health, RePORTER application 9856979, Dissecting the means by which type 3 substrates are defined & secreted (5R01AI128360-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9856979. Licensed CC0.

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