Jakovac Hrvoje, Ćuk Mira, Trobonjača Zlatko, Mrakovčić-Šutić Ines, Radošević-Stašić Biserka
Department of Physiology and Immunology, Medical Faculty, University of Rijeka, Rijeka, Croatia.
Histol Histopathol. 2015 Aug;30(8):931-43. doi: 10.14670/HH-11-597. Epub 2015 Feb 19.
Glycoprotein 96 (gp96) is an endoplasmic reticulum (ER)-resident heat shock protein. It controls the folding of nascent membrane-spanning and secretory proteins, participates in stress-induced unfolded protein response (UPR) and in pathways leading to proteolysis of damaged proteins through ER-associated degradation pathways and chaperone-mediated autophagy. In addition, gp96 controls the steroid biosynthesis and Ca²⁺ homeostasis and participates in insulin-IGF/signaling pathways. Besides, owing to its peptide chaperone capacity and ability to interact with antigen-presenting cells, gp96 has been implicated in priming of innate and adaptive immunity. In an attempt to visualize the intensity of ER-stress in thymus and possible participation of gp96 in generation of auto-reactive T cell clones that were detected in regenerating liver, in this study we investigated the dynamics of gp96 expression in partially hepatectomized (pHx) and sham Hx mice. Simultaneously, we detected the thymic expression of receptors responsible for endocytosis of gp96-chaperoned peptides (CD91) and intracellular activation of ER-stress pathways (TLR2), as well as the expression of TGF-ß and the distribution of CD4+CD25+FoxP3+ cells. The data have shown that both pHx and sham Hx induced an accelerated apoptosis and hypoplasia in thymus. Partial Hx induced, however, a higher expression of gp96, the translocation of the CD91, TLR2 and TGF-ß immunostaining from medulla to cortex and an appearance of Treg cells. The data show that pHx triggers in thymus the ER-stress and UPR response and suggest that gp96 participates in the generation of natural Treg cells, which might be involved in the control of liver regeneration in the periphery.
糖蛋白96（gp96）是一种内质网（ER）驻留热休克蛋白。它控制新生跨膜蛋白和分泌蛋白的折叠，参与应激诱导的未折叠蛋白反应（UPR），并通过内质网相关降解途径和伴侣介导的自噬参与导致受损蛋白降解的途径。此外，gp96控制类固醇生物合成和Ca²⁺稳态，并参与胰岛素-IGF/信号通路。此外，由于其肽伴侣能力和与抗原呈递细胞相互作用的能力，gp96与先天免疫和适应性免疫的启动有关。为了观察胸腺中内质网应激的强度以及gp96在再生肝脏中检测到的自身反应性T细胞克隆生成中的可能参与情况，在本研究中，我们调查了部分肝切除（pHx）和假手术肝切除（sham Hx）小鼠中gp96表达的动态变化。同时，我们检测了负责gp96伴侣肽内吞作用的受体（CD91）的胸腺表达、内质网应激途径的细胞内激活（TLR2），以及TGF-β的表达和CD4+CD25+FoxP3+细胞的分布。数据表明，pHx和假手术肝切除均诱导胸腺加速凋亡和发育不全。然而，部分肝切除诱导了更高的gp96表达、CD91、TLR2和TGF-β免疫染色从髓质向皮质的移位以及调节性T细胞的出现。数据表明，pHx在胸腺中触发内质网应激和UPR反应，并表明gp96参与天然调节性T细胞的生成，这可能参与外周肝脏再生的控制。
