Biology subjects

Hoffman, C. L.

Publications and source records attributed to Hoffman, C. L..

3 recordsLinked to original sources

bioRxiv2024

Pemphigus vulgaris autoantibodies induce an ER stress response

Desmosomes are intercellular junctions that mediate cell-cell adhesion and are essential for maintaining tissue integrity. Pemphigus vulgaris (PV) is an autoimmune epidermal blistering disease caused by autoantibodies (IgG) targeting desmoglein 3 (Dsg3), a desmosomal cadherin. PV autoantibodies cause desmosome disassembly and loss of cell-cell adhesion, but the molecular signaling pathways that regulate these processes are not fully understood. Using high- resolution time-lapse imaging of live keratinocytes, we found that ER tubules make frequent and persistent contacts with internalizing Dsg3 puncta in keratinocytes treated with PV patient IgG. Biochemical experiments demonstrated that PV IgG activated ER stress signaling pathways, including both IRE1 and PERK pathways, in cultured keratinocytes. Further, ER stress transcripts were upregulated in PV patient skin. Pharmacological inhibition of ER stress protected against PV IgG-induced desmosome disruption and loss of keratinocyte cell-cell adhesion, suggesting that ER stress may be an important pathomechanism and therapeutically targetable pathway for PV treatment. These data support a model in which desmosome adhesion is integrated with ER function to serve as a cell adhesion stress sensor that is activated in blistering skin disease.

cell biology↗

bioRxiv2023

Microbial siderophore production is tightly coupled to iron in hydrothermal plumes

Hydrothermal vents have emerged as an important source of iron to seawater, yet only a subset of iron is soluble and persists long enough to be available for surface biological uptake. The longevity and solubility of iron in seawater is governed by strong organic ligands, like siderophores, that are produced by marine microorganisms and are a part of the oceans dissolved iron-binding ligand pool. These ligands have been hypothesized to aid in the persistence of dissolved iron in hydrothermal environments. To explore this hypothesis, we measured iron, iron-binding ligands, and siderophores from 11 geochemically distinct sites along a 1,700 km section of the Mid-Atlantic Ridge. Siderophores were found in hydrothermal plumes at all sites, with proximity to the vent playing an important role in dictating siderophore types and diversity. The notable presence of amphiphilic siderophores may point to microbial utilization of siderophores to access particulate hydrothermal iron, and the exchange of dissolved and particulate iron. The tight coupling between strong ligands and dissolved iron within neutrally buoyant plumes across six distinct hydrothermal environments, and the presence of dissolved siderophores with siderophore-producing microbial genera, suggests that biological production of siderophores exerts a key control on hydrothermal dissolved iron concentrations.

biochemistry↗

bioRxiv2019

Host mucin is subverted by Pseudomonas aeruginosa during infection to provide free glycans required for successful colonization

The mucosal barrier, found lining epithelial cells, serves multiple functions in a range of animals. The major structural components of mucus are mucins, which are heavily glycosylated proteins that are either membrane bound or secreted by the epithelial cells. Mucins are key components of the innate immune system, as they are involved in the clearance of pathogens from the airways and intestines, and their expression is typically upregulated upon epithelial cell exposure to a variety of pathogens. In this study, we identified the mucin MUL-1 as an innate immune factor that appears to be utilized by P. aeruginosa to colonize hosts. We found that while the expression of several mucins, including MUL-1, increased upon P. aeruginosa infection of the nematode Caenorhabditis elegans, silencing of or deletion of mul-1 resulted in enhanced survival and reduced bacterial accumulation. P. aeruginosa required host sialidase CTSA-1.1 to use mucin-derived glycans to colonize the host, while sialidase-encoding bacteria required host MUL-1 but not CTSA-1.1 to cause a lethal infection. This role of mucins and free glycans in host-pathogen interaction appears to be conserved from C. elegans to humans, as P. aeruginosa binding to human lung epithelial cells was also enhanced in the presence of free glycans, and free glycans reversed the binding defect of P. aeruginosa to human lung cells lacking the mucin MUC1.\n\nAuthor SummaryThe gastrointestinal, respiratory, reproductive, and urinary tracts, are large surfaces exposed to the exterior environment and thus, these mucosal epithelial tissues serve as primary routes of infection. One of the first lines of defense present at these barriers is mucus, which is a highly viscous material formed by mucin glycoproteins. Mucins serve various functions, but importantly they aid in the clearance of pathogens and debris from epithelial barriers and serve as innate immune effectors. In this study, we describe the ability of Pseudomonas aeruginosa to utilize mucin-derived glycans to colonize the intestine and ultimately cause death in Caenorhabditis elegans. We also show conserved mechanisms of P. aeruginosa virulence traits, by demonstrating that free glycans alter the ability of the bacteria to bind to human lung alveolar epithelial cells. Over the course of host-pathogen evolution, pathogens seem to have evolved to use mucins for their own advantage, and thus one of the biggest questions is which party benefits from pathogen-mucin binding. By gaining a better understanding of pathogen-mucin interactions, we can better protect against pathogen infection.

microbiology↗