# Protein Sialylation and De-Sialyation in Cell Surface Glycoprotein Homeostasis and Disease

> **NIH NIH R01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2024 · $487,500

## Abstract

SUMMARY
Protein sialylation is a post-translational modification produced by members of a family of sialyltransferases.
We recently discovered that the resulting sialic acid linkages are involved in the regulation of glycoprotein
abundance and function in an intrinsic homeostatic mechanism that is targeted by multiple pathogens.
Environmental factors are dominant in the origins of the human Inflammatory Bowel Diseases (IBDs) and
seasonal bacterial infections have been implicated. We therefore developed a mouse model of repeated
human food poisoning comprised of recurrent low-titer non-lethal gastric infections of the Gram-negative
bacterial pathogen Salmonella enterica Typhimurium (ST), a leading cause of human foodborne illness
worldwide. In this unique model, the ST pathogen was rapidly cleared by the host, however a progressively
severe and persistent colitis developed similar to Ulcerative Colitis (UC). We demonstrated that pathogenesis
was linked to the disabling of a protective mechanism in the host involving the anti-inflammatory Intestinal
Alkaline Phosphatase (IAP) glycoprotein enzyme produced by enterocytes. Recurrent ST infections resulted in
Toll-like receptor-4 (Tlr4) induction of neuraminidase (Neu) activity and host Neu3 abundance with nascent IAP
de-sialylation and endocytic degradation, thereby reducing IAP half-life, abundance, and function. IAP
deficiency was similarly acquired in mice lacking the ST3Gal6 sialyltransferase resulting in spontaneous colitis.
The disease mechanism in both cases was Tlr4-dependent and linked to reduced dephosphorylation and
detoxification of the lipopolysaccharide-phosphate produced by commensal bacteria of the colon. In humans,
similar modulation of IAP and Neu3 have been reported in colitis, and genetic deficiency of IAP causes colitis,
supporting the rationale for ongoing clinical trials of IAP augmentation and neuraminidase inhibition. However,
the key involvement of Neu3 remains to be established. Research proposed herein will directly test the role of
host Neu3 in the onset and progression of colitis among Neu3-null mice. In addition, the possibility that other
enteric Gram-negative pathogens similarly provoke IAP deficiency will be investigated with the development of
other recurrent non-lethal gastric infection models using related Gram-negative enteric pathogens including the
hypervirulent Salmonella enterica Choleraesuis serovar. We have recently measured elevated Neu activity and
Neu3 protein abundance in the colon during recurrent ST infection associated with the de-sialylation of Mucin–
2 (Muc2), the major glycoprotein component of the protective mucin barrier. The mechanism of erosion of the
mucin barrier in colitis remains unknown but plays a large role in pathogenesis. We have recently linked
erosion of the mucin barrier to reductions of Muc2 protein sialylation, likely by ST3Gal6. Remarkably, Neu
treatment increases Muc2 proteolysis with reduced Muc2 abundance. Research proposed he...

## Key facts

- **NIH application ID:** 10808043
- **Project number:** 5R01AI151371-04
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** JAMEY MARTH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $487,500
- **Award type:** 5
- **Project period:** 2021-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10808043

## Citation

> US National Institutes of Health, RePORTER application 10808043, Protein Sialylation and De-Sialyation in Cell Surface Glycoprotein Homeostasis and Disease (5R01AI151371-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10808043. Licensed CC0.

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