In TCR-Stimulated T-cells, N-ras Regulates Specific Genes and Signal Transduction Pathways

Abstract

It has been recently shown that N-ras plays a preferential role in immune cell development and function; specifically: N-ras, but not H-ras or K-ras, could be activated at and signal from the Golgi membrane of immune cells following a low level T-cell receptor stimulus. The goal of our studies was to test the hypothesis that N-ras and H-ras played distinct roles in immune cells at the level of the transcriptome. First, we showed via mRNA expression profiling that there were over four hundred genes that were uniquely differentially regulated either by N-ras or H-ras, which provided strong evidence in favor of the hypothesis that N-ras and H-ras have distinct functions in immune cells. We next characterized the genes that were differentially regulated by N-ras in T cells following a low-level T-cell receptor stimulus. Of the large pool of candidate genes that were differentially regulated by N-ras downstream of TCR ligation, four genes were verified in qRT-PCR-based validation experiments (Dntt, Slc9a6, Chst1, and Lars2). Finally, although there was little overlap between individual genes that were regulated by N-ras in unstimulated thymocytes and stimulated CD4+ T-cells, there was a nearly complete correspondence between the signaling pathways that were regulated by N-ras in these two immune cell types.

The Differential Palmitoylation States of N‐Ras and H‐Ras Determine Their Distinct Golgi Subcompartment Localizations

“…Consistent with this, our group has previously shown through mRNA expression profiling that N-Ras and H-Ras activate different downstream signaling programs in immune cells (Lynch SJ, et al ., 2013). Overall, these results support the hypothesis that differential Ras isoform Golgi membrane localization translates to differential Golgi signaling.…”

“…Whatever the cause of the differential localization of N-Ras and H-Ras within the Golgi, this feature of Ras biology may have implications in signaling if relevant effectors are also asymmetrically distributed within the Golgi, especially as Golgilocalized Ras proteins have been previously shown to be able to signal from this organelle (Chiu et al, 2002). Consistent with this, our group has previously shown through mRNA expression profiling that N-Ras and H-Ras activate different downstream signaling programs in immune cells (Lynch SJ et al, 2013). Overall, these results support the hypothesis that differential Ras isoform Golgi membrane localization translates to differential Golgi signaling.…”

Protons to Patients: targeting endosomal Na+/H+ exchangers against COVID‐19 and other viral diseases

“…An important therapeutic advantage of targeting eNHEs is that, in addition to potentially inhibiting a wide array of viruses, their anti‐inflammatory and immunoregulatory effects may modulate both the innate and adaptive immune response. For example, NHE6 is a known downstream neuroblastoma RAS viral oncogene homolog effector in T cells that mediates protection against viral infections [ 66 , 67 ]. Similarly, NHE9 regulates T‐cell function by modulating its response to IFNβ and can thus induce its own expression [ 28 ].…”

Identification of Exosomal miRNAs in Rats With Pulmonary Neutrophilic Inflammation Induced by Zinc Oxide Nanoparticles

“…Chst1 is modulated by four miRNAs, including miR-30b-5p, miR-19a-3p, miR-130a-3p, and miR-134-5p. Chst1 encodes the enzyme CHST1 (carbohydrate sulfotransferase 1), a golgi-localized, transmembrane sulfotransferase that sulfonates specific O-linked carbohydrate side chains on lipids and proteins (Lynch et al, 2014 ). CHST1 may be expressed by neutrophils and is associated with the generation of L-selectin ligands.…”