# Regulation of protein secretion in human gut commensals

> **NIH NIH F32** · YALE UNIVERSITY · 2022 · $67,174

## Abstract

Project Summary
 Commensal bacteria in the human intestinal tract provide numerous benefits to their hosts, from digestion of
foods inaccessible to the host to protection against pathogen invasion. Many host-microbiome interactions are
mediated by bacterial proteins secreted into the gut (the secretome), but regulation and coordination of this
process has not been studied. This proposal focuses on the dominant gut genus Bacteroides to test the
hypothesis that these organisms use central mechanisms to control deployment of secreted proteins. One clue
comes from studies of commensal-encoded toxins: two secreted toxins with no similarities in sequence or
targets both use the same surface-associated cysteine protease to orchestrate their secretion. Homologs of
this cysteine protease (but not its targets) are conserved across Bacteroides, suggesting a broader role for
these enzymes in regulating protein secretion. This proposal will use an innovative N-terminome proteomic
approach to determine the repertoire of protease substrates in Bacteroides and establish whether protease
homologs share targets within and between species. Complementary studies in gnotobiotic mice will determine
the contribution of protease processing to the in vivo secretome. This proposal will also use genetics,
anaerobic microbiology, and gnotobiotics to elucidate environmental cues and signal transduction pathways
that regulate protease expression. This will determine how these proteases might coordinate release of waves
of secreted proteins in response to environmental signals in the gut. If successful, these studies will uncover
fundamental mechanisms for secretome regulation in the microbiome, with implications for host-microbiome
interactions and bioengineering therapeutic enzyme delivery in the gut.
 This proposal also presents a detailed training plan that will allow the candidate to develop new skills
required for career advancement. This research will be conducted at the highly collaborative and
multidisciplinary Microbial Sciences Institute (MSI) at Yale University. The sponsor has an established track
record of mentorship, and the lab and the MSI provide state-of-the-art facilities. The diverse expertise of peers
and faculty at MSI, ranging from chemists, biochemists, and geneticists, will support the candidate's research
goals. A mentoring committee will provide technical guidance for the project and will support the candidate's
career development. The candidate will also complete training in mentoring and teaching from the Poorvu
Center for Teaching and Learning and the Yale Postdoctoral Association, and he will put this training into
practice by mentoring students in their local science fair projects. By presenting his work to peers at Yale
University and in conferences, the candidate will foster his communication skills and build a network of
colleagues. Together, this training plan will build the skillset and connections required to succeed as an
independent inve...

## Key facts

- **NIH application ID:** 10388882
- **Project number:** 1F32GM145116-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Brent W Anderson
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $67,174
- **Award type:** 1
- **Project period:** 2022-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10388882

## Citation

> US National Institutes of Health, RePORTER application 10388882, Regulation of protein secretion in human gut commensals (1F32GM145116-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10388882. Licensed CC0.

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