Biology subjects

Gomer, R.

Publications and source records attributed to Gomer, R..

4 recordsLinked to original sources

bioRxiv2025

Neuraminidase 3 acts in a rapid translation-based positive feedback loop to activate TGF-β1

Fibrosis appears to be an out-of-control wound healing response that drives a progressive formation of scar tissue in an organ. A key profibrotic cytokine, transforming growth factor beta-1 (TGF-{beta}1), upregulates levels of the fibrosis-driving sialidase, neuraminidase 3 (NEU3), and NEU3 can activate latent TGF-{beta}1 to release active TGF-{beta}1 from the sequestering LAP peptide. In the mouse bleomycin model of pulmonary fibrosis, NEU3 is both necessary and sufficient for fibrosis. In this report, we find that NEU3 levels increase both intracellularly and extracellularly in cultures of human lung fibroblasts within 5 minutes of TGF-{beta}1 exposure. This effect is driven by an increase in translation and is independent of new transcription, supporting a model where TGF-{beta}1 causes a pool of weakly translated NEU3 mRNA to increase translation. The RNA helicase DEAD-box helicase 3 (DDX3) mediates NEU3 translation. TGF-{beta}1 induces dephosphorylation of DDX3 within two minutes, and DDX3 inhibitors block the rapid NEU3 upregulation. The NEU3-TGF-{beta}1-NEU3 positive feedback loop is activated within 5 minutes, and the remaining LAP fragment (after NEU3 activation of the latent TGF-{beta}1 complex) appears to potentiate NEU3 upregulation. This feedback loop is blocked by NEU3 inhibitors. These findings suggest that NEU3 is a rapidly acting amplifier of TGF-{beta}1 signaling, likely through TGF-{beta}1-mediated dephosphorylation of DDX3, and this mechanism may be associated with an early tissue-healing response mechanism that drives the initiation and progression of fibrosis.

cell biology↗

bioRxiv2025

An extracellular matrix coating similar to articular cartilage inhibits the differentiation of myofibroblasts and limits the development of implant-induced fibrosis

Fibrosis is involved in 45% of deaths in the United States, with no treatment options to reverse progression of the disease. Implantable devices (such as joint replacements, chips, stents, artificial organs, biosensors, catheters, heart valves, scaffolds for tissue engineering, etc.) can trigger a foreign body response, in which fibrotic tissue covers the implant and impedes its function. Myofibroblast are a key cellular component of scar tissue. To explore the relationship between extracellular matrix-based coatings and fibrosis, we coated tissue-culture surfaces using a library of extracellular matrix (ECM) proteins and then performed an in-vitro screen for myofibroblast differentiation on the coated surfaces as an indicator of fibrotic potential. The protein and proteoglycan components of cartilage (collagen II, biglycan, decorin, and chondroitin sulfate) were individually anti-fibrotic. Further, mixtures of collagen II, biglycan, decorin, and chondroitin sulfate inhibited myofibroblast differentiation to a greater degree than collagen II, biglycan, decorin, or chondroitin sulfate as individual coatings. Next, we performed an in-vivo model of a foreign-body response. Implanting an uncoated implant subcutaneously into mice resulted in a thicker layer of fibrotic scar tissue than implants coated with a cartilage-like ECM mixture. Our results indicate that the ECM microenvironment is key to the initiation, progression, and maintenance of fibrosis.

immunology↗

bioRxiv2024

PTEN and the PTEN-like phosphatase CnrN have both distinct and overlapping roles in a Dictyostelium chemorepulsion pathway

The directed movement of eukaryotic cells is crucial for processes such as embryogenesis and immune cell trafficking. The enzyme Phosphatase and tensin homolog (PTEN) dephosphorylates phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] to phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. Dictyostelium discoideum cells require both PTEN and the PTEN-like phosphatase CnrN to locally inhibit Ras activation to induce biased movement of cells away from the secreted chemorepellent protein AprA. Both PTEN and CnrN decrease basal levels of PI(3,4,5)P3 and increase basal numbers of macropinosomes, and AprA prevents this increase. AprA requires both PTEN and CnrN to increase PI(4,5)P2 levels, decrease PI(3,4,5)P3 levels, inhibit proliferation, decrease myosin II phosphorylation, and increase filopod sizes. AprA causes PTEN, similar to CnrN, to localize to the side of the cell towards AprA in an AprA gradient. However, PTEN and CnrN also have distinct roles in some signaling pathways. PTEN, but not CnrN, decreases basal levels of PI(4,5)P2, AprA requires PTEN, but not CnrN, to induce cell roundness, and CnrN and PTEN have different effects on the number of filopods and pseudopods, and the sizes of filopods. Together, our results suggest that CnrN and PTEN play unique roles in D. discoideum signaling pathways, and possibly dephosphorylate PI(3,4,5)P3 in different membrane domains, to mediate chemorepulsion away from AprA.

cell biology↗

bioRxiv2022

Dictyostelium discoideum cells sense their local density and retain nutrients when the cells are about to overgrow their food source

Dictyostelium discoideum is a unicellular eukaryote that eats bacteria, and eventually overgrows the bacteria. D. discoideum cells accumulate extracellular polyphosphate (polyP), and the polyP concentration increases as the local cell density increases. At high cell densities, the correspondingly high extracellular polyP concentrations allow cells to sense that they are about to overgrow their food supply and starve, causing the D. discoideum cells to inhibt their proliferation. In this report, we show that high extracellular polyP inhibits exocytosis of undigested or partially digested nutrients. PolyP decreases cell membrane fluidity and plasma membrane recycling, and this requires the G protein-coupled polyP receptor GrlD, the polyphosphate kinase Ppk1, and the inositol hexakisphosphate kinase I6kA. PolyP did not affect random cell motility, cell speed, or F-actin levels. PolyP decreased membrane saturated fatty acids and altered lipid and protein contents in detergent-insoluble lipid microdomains. Together, these data suggest that D. discoideum cells use polyP as a signal to sense their local cell density and reduce cell membrane fluidity and membrane recycling, perhaps as a mechanism to retain ingested food when the cells are about to starve.

cell biology↗