Biology subjects

Wuest, T. R.

Publications and source records attributed to Wuest, T. R..

3 recordsLinked to original sources

bioRxiv2019

Neutrophilic granule protein is a novel murine LPS antagonist

NGP was previously reported as a granular protein of neutrophils in mouse but the function has not been known clearly. We found the presence of the possible signal peptide in NGP and we hypothesized this protein is being secreted to the blood stream. Since this protein has sequence similarity with an antimicrobial protein cathelicidin, we observed the aspect of inflammation of NGP. Interestingly, NGP interacts with the complex of LPS and LBP and blocked the inflammatory function of NGP. This inhibitory effect of NGP was through the inhibition of LPS-LBP complex to interact with TLR4 molecule. Furthermore, the inhibitory function of NGP could be repeated on the inflammatory effect of LPS in both in vitro and in vivo. With these findings, we report NGP is a novel secretory protein to mask LPS and inhibits its function.

immunology↗

bioRxiv2019

Oxygen tension regulates lysosomal activation and receptor tyrosine kinase degradation

Oxygen sensing is crucial for adaptation to variable habitats and physiological conditions. Low oxygen tension, or hypoxia, is a common feature of solid tumors and hypoxic tumors are often more aggressive and resistant to therapy. Here we show that, in mammalian tissue culture cells, hypoxia suppressed lysosomal acidification/activation and receptor tyrosine kinase (RTK) degradation. Hypoxia down-regulated mTORc1, reducing its ability to activate transcription factor EB (TFEB), a master regulator of v-ATPase, the lysosomal proton pump. Hypoxia prevented epidermal growth factor receptor (EGFR) degradation in tumor tissues, whereas activation of lysosomes enhanced tumor cell response to anti-EGFR treatment. Our results link oxygen tension and lysosomal activity, provide a molecular explanation of the malignant phenotype associated with hypoxic tumors, and suggest activation of lysosomes may provide therapeutic benefit in RTK-targeted cancer therapy.\n\nOne Sentence SummaryHypoxia suppresses lysosomal activation and proteolysis.

cell biology↗

bioRxiv2019

Vav1 is essential for HIF-1α activation in vascular response to ischemic stress

Vascular response to hypoxia is a major determinant of organ function under stress, which is particularly critical for vital organs such as the heart. This study identifies Vav1 as a key vascular regulator of hypoxia. Vav1 is present in vascular endothelium and is essential for HIF-1 activation under hypoxia. It regulates HIF-1 stabilization through the p38/Siah2/PHD3 pathway. Consequently, Vav1 deficient mice are predisposed to sudden death under cardiac ischemia with increased coronary endothelial apoptosis. Moreover, Vav1 binds to VEGFR1 that carries Vav1 to lysosomes for degradation in normoxia. Hypoxia upregulates Vav1 through inhibition of protein degradation. These findings reveal that regulation of Vav1 by hypoxia is analogous to HIF-1 regulation. Both proteins are constitutively produced allowing for rapid responses when stress occurs, and constantly degraded in normoxia. Hypoxia stabilizes Vav1, which is required for HIF-1 accumulation. Together they mediate the vascular response to hypoxia and maintain tissue homeostasis.

cancer biology↗