Reduced stress tolerance of glutamine-deprived human monocytic cells is associated with selective down-regulation of Hsp70 by decreased mRNA stability

In critically ill patients, clinicians observe a reverse correlation of survival and a decreased plasma concentration of the most abundant free amino acid, glutamine (Gin). However, in this context, the role of Gin remains largely elusive. Gin is used as an energy substrate by monocytes. Gin deprivation of these cells results in an increased susceptibility to cell stress and apoptosis, as well as in a reduced responsiveness to pro-inflammatory stimuli. We performed a systematic study to elucidate the molecular mechanism by which Gin depletion affects the heat stress response of the monocytic cell line U937. Proteomic analysis revealed that Gin depletion was associated with specific changes in the protein expression pattern. However, the overall level of tRNA-bound Gin remained unaffected. The stress protein heat shock protein (Hsp) 70 showed the highest reduction in protein synthesis. This was due to enhanced mRNA decay during Gin starvation while the transcriptional and the translational control of Hsp70 expression remained unchanged. A physiological Gin concentration and above was found to be necessary for maximum Hsp70 accumulation upon heat shock. Thus, the study shows a specific link between Gin metabolism and the regulation of heat shock proteins.