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Morphogenetic and immunoregulatory roleS of endoplasmic reticulum resident heat shock protein gp96

Heat shock proteins (HSPs) are phylogenetically conserved proteins, present in all prokaryotes and eukaryotes that are involved in various physiological and pathological processes. According to their function and size, or cellular localization, they are classified into major classes (small HSPs, HSP40, 60, 70, 90, and 110 families) and several members of a family. Gp96 (known also as glucose-regulated protein 94) is the endoplasmic reticulum (ER)-resident protein belonging to the HSP90 family. It is upregulated in response to glucose starvation and other stressful stimuli that disrupt protein synthesis in the ER, acting as a molecular chaperon involved in the correction of unfolded proteins, in the activation of proteasome-dependent ER-associated degradation of the misfolded proteins and in activation of protein translation that modulate the polypeptide traffic into the ER. In addition, it has been implicated in antigen presentation and MHC class I and II upregulation, in the activation and maturation of dendritic cells and proinflammatory cytokine secretion, as well as in chaperoning of Toll-like receptors, acting as a "danger signal" to the innate and adaptive immunity. Moreover, owing to its specific function in Ca2+ homeostasis and in the insulin-IGF/signaling pathways it was proposed that gp96 participates in mechanisms that are critical for cell growth, differentiation and responses to ER stress. To underline some aspects of these functions, in this survey we will present the data showing the expression of gp96 in the conditions of: 1) normal growth (liver regeneration after partial hepatectomy, syngeneic pregnancy, fetal organogenesis), 2) stress and ageing and 3) autoimmunity (chronic relapsing experimental autoimmune encephalomyelitis ; CR-EAE). Tissue expression of gp96 protein and mRNA was estimated in the liver, thymus and spleen and the data were correlated with phenotype and cytotoxicity of hepatic and splenic mononuclear lymphatic cells against the NKT and NK-sensitive targets. In the model of CR-EAE gp96 expression in the brain was correlated with the intensity of clinical symptoms. The data have shown that gp96 is highly upregulated in fastly proliferating and remodeling tissues (in regenerating liver, at the fetoplacental barrier, during fetal organogenesis), as well as in healing tissues after autoimmune attack (in the brain and spinal cord during the remission phases of EAE). Enhanced level of gp96 expression was also found in the thymus of aged and stress-exposed mice. Moreover, the kinetic studies made in the model of liver regeneration showed that gp96 upregulation was followed by maturation of dendritic cells, accumulation of CD3intermediate/NK1.1+/CD69+cells in the liver and CD4+CD25+Fox3+ cells in the liver and thymus, as well as by augmentation of NKT and NK-mediated cytotoxicity in the liver and in the spleen. The data imply that during the disturbance of morphostasis gp96 may serve as a natural adjuvant for chaperoning antigenic self peptides into the immune surveillance pathways, resulting in activation of autoreactive NKT, which in cooperation with Treg cells participate in more or less successful reestablishment of self tolerance (Supported by grant 0621341-1337 from Croatian Ministry of Science).

Liver regeneration; syngeneic pregnancy; fetal organogenesis; stress and ageing; autoimmunity

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