SVIP ADLI PROTEİNİN ADRENAL BEZDEKİ ROLÜNÜN HÜCRE KÜLTÜR MODELİNDE İNCELENMESİ
Project no. 244 · Status: Kapanmış · 2016
Summary
SVIP is the first endogenous inhibitor of ERAD, which is the ER stress response mechanism that allows misfolded proteins to break down and only correctly folded proteins to reach their place of duty (Ballar et al., 2007). Apart from its role as an ERAD inhibitor, SVIP is known to play a regulatory role in autophagy by modulating the LC3 process, p62 expression, and clustering of polyubiquitinated proteins (Wang et al., 2011). We have demonstrated with preliminary trials that SVIP expression levels occur especially in the adrenal cortex region where steroid hormone synthesis is intense. It is known that the ERAD system is responsible for physiological levels of not only misfolded proteins but also proteins that are correctly folded. The most common example is that it regulates the levels of the HMG-Coa enzyme, the rate limiting enzyme of the synthesis of cholesterol, which is the starting material of steroid hormone synthesis. Degradation of HMG-CoA reductase by ERAD is found in both mammalian and yeast cells as an important feedback inhibition system in sterol homeostasis. It is found in both mammalian and yeast cells as an important feedback inhibition system. HMG-CoA reductase is not the only protein that functions in sterol synthesis and is targeted by ERAD, it has been reported that Insig1 and squalene monooxygenase are also substrates regulated by ERAD (Foresti et al., 2013; Morris et al., 2014) (Shmueli et al., 2009) (Song et al., 2005). It has also been shown that gp78, which is the ubiquitin ligase enzyme that functions in ERAD, plays a role in the destruction of Apolipoprotein B100, one of the main proteins of LDL-VLDL lipoproteins, which is involved in cholesterol transport (Liang et al., 2003). It has been suggested that autophagy targets steroid-producing organelles (mitochondria and flat ER) in organs that secrete steroid hormones, such as the testis and adrenal cortex (Weckman et al., 2014). In a study, it was observed that the expression of the STAR protein was decreased in the testosterone-synthesizing Leydig cells of rats treated with the autophagy inhibitor wortmanin, and accordingly, testosterone production decreased (Li et al., 2011). It has also been reported that the deficiency of Beclin1, one of the autophagy proteins, reduces progesterone synthesis in the mouse ovary (Gawriluk et al., 2014). In another study showing the importance of the role of autophagy in endocrine glands, dense ubiquitin-positive protein aggregate formation was observed in Atg5 - / - mice, especially in the liver, pituitary anterior lobe and adrenal cortex (Hara et al., 2006). Although it is our primary goal to investigate the effects of SVIP on sterol metabolism over ERAD within the scope of the thesis, the effect of SVIP on autophagy within the scope of BAP has been investigated due to the possibility that the role of SVIP is independent of ERAD.