System A regulation under stress conditions: molecular mechanisms and signaling pathways

Abstract

During my PhD program I have studied the regulation of SNAT2, the ubiquitously expressed system A transporter, under stress conditions. A marked stimulation of system A transport activity is observed upon either amino acid starvation or hypertonic stress. The results obtained demonstrated that, in cultured human fibroblasts, increased abundance of SNAT2 carriers on the plasma membrane accounts for system A transport stimulation during osmotic stress and amino acid starvation. Although both these stresses are associated to the increased abundance of SNAT2 mRNA the signalling pathways involved are different. SNAT2 induction by amino acid starvation involves signalling via the phosphorylation of eIF2alpha, while induction by osmotic stress seems exquisitely TonEBP-dependent. Moreover, the results demonstrate that, upon amino acid starvation, when cap-dependent translation decreases, the SNAT2 mRNA is translated through an IRES located within the 5’UTR, the activity of SNAT2 IRES under osmotic stress conditions has not been yet demonstrated. The induction of system A is a complex mechanism that involves different signalling pathways, increased gene expression, post-transcriptional modifications, cap-independent translation, and protein relocalization. Such a fine and multifaceted regulation points to the importance of this system to counteract physiological or pathological situations that may alter cellular homeostasis.