Endoplasmic Reticulum-Associated Degradation (ERAD)

The newly synthesized proteins are kept in the endoplasmic reticulum (ER) until their maturation is completed. The accurate protein folding is vital for homeostasis, but this process is error-prone since it is chemically complicated. Aberrant folding may result in aggregates having a toxic gain of function or may lead to a loss of protein function; therefore, protein misfolding can lead to several pathologies. The ER protein quality control mechanism monitors the fidelity of protein folding. Those proteins that fail to fold or assemble properly are subjected to degradation via a process known as ER-associated degradation (ERAD). Besides clearing proteins having folding problems, ERAD is also known to regulate the levels of some physiological proteins including 3-hydroxy-3-methylglutaryl-coenzymeA reductase (HMGR) catalyzing the rate-limiting step of cholesterol biosynthesis. ERAD is a complex, multistep process starting with the recognition and targeting of substrates, followed by ubiquitination, retrotranslocation and proteasomal degradation. A large number of ERAD factors functioning in different molecular machineries increases the complexity of mammalian ERAD. ERAD is fundamental for human health and there is increasing evidence linking ERAD with various diseases. Here, the different modules/machineries of the ERAD process together with its tight regulation will be discussed

SVIP Induces Localization of p97/VCP to the Plasma and Lysosomal Membranes and Regulates Autophagy

The small p97/VCP-interacting protein (SVIP) functions as an inhibitor of the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway. Here we show that overexpression of SVIP in HeLa cells leads to localization of p97/VCP at the plasma membrane, intracellular foci and juxtanuclear vacuoles. The p97/VCP-positive vacuolar structures colocalized or associated with LC3 and lamp1, suggesting that SVIP may regulate autophagy. In support of this possibility, knockdown of SVIP diminished, whereas overexpression of SVIP enhanced LC3 lipidation. Surprisingly, knockdown of SVIP reduced the levels of p62 protein at least partially through downregulation of its mRNA, which was accompanied by a decrease in starvation-induced formation of p62 bodies. Overexpression of SVIP, on the other hand, increased the levels of p62 protein and enhanced starvation-activated autophagy as well as promoted sequestration of polyubiquitinated proteins and p62 in autophagosomes. These results suggest that SVIP plays a regulatory role in p97 subcellular localization and is a novel regulator of autophagy

ERAD'ın androjen temelli hormonal regülasyonunun ve bu regülasyonun prostat kanseri gelişimindeki rolünün araştırılması

Endoplazmik retikulum (ER) ökaryotik hücrelerdeki tüm membran ve salgı proteinlerinin üçte birinin sentezlenerek, uygun konformasyonlarına ulaşmasına aracılık eden kompleks bir merkez olarak görev yapmaktadır. ER’de organize olan “kalite kontrol mekanizması”; nihai formuna ulaşamayan proteinlerin ER’den çıkışını engelleyerek, ER ilişkili protein yıkım yolağıyla (ERAD) istenmeyen bu proteinlerin proteozoma hedeflenmesini gerçekleştirerek oluşabilecek proteotoksik etkilere karşı hücreleri korumaktadır. Bu mekanizmanın aynı zamanda kolesterol metabolizması enzimi HMGKoA redüktaz ile sitokrom p450 monooksijenaz gibi hücreler için kritik öneme sahip birçok proteinin bazal düzeylerini ayarladığı da bilinmektedir. Genotoksik etkiler, mutasyonlar ya da kimyasal ajanlara maruziyet sonrası ERAD’ın işleyişinde gözlenen aksamaların hücrelerde bir çok patofizyolojik sonucu doğurduğu bilinmektedir. IBMPFD gibi çoklu organ yetmezliklerinin görüldüğü sendromlar, Huntington, Alzheimer, Parkinson hastalıkları gibi nörodejeneratif rahatsızlıklar, diabetes mellitus, retinitis pigmentosa gibi fizyolojik bozukluklar ve bir çok kanser tipinin gelişimi ERAD ile ilişkilendirilmiştir. Günün en yaygın hastalığı olan kanser ile ERAD arasındaki ilişkiyi belirlemek özellikle önemlidir. Prostat kanseri, erkeklerde cilt kanseri sonrası en sık görülen kanser türleri arasında yer aldığından, birçok araştırma grubunun ilgi odağı haline gelmiştir. Bu nedenle birçok hücresel moleküler mekanizmanın prostat kanseri ile ilişkisine yönelik araştırma sayısı her geçen gün artış göstermektedir. Prostat karsinogenezi ile ERAD üyeleri arasındaki ilişkinin aydınlatılmasını amaçlayan çalışmamızın in vivo kısmında 9 sağlıklı ve 39 prostat kanseri olan toplam 48 bireye ait örneklerde ERAD mekanizmasında farklı basamaklarda görev alan Hrd1, gp78, p97/VCP, SVIP, Derlin1, Ufd1, Npl4, OS9 ve UFD2A’nın gen ifade profillerinin kanserleşmeyle olan ilişkisi değerlendirildi. Bulgularımız prostat karsinogenezi ile korele olarak ERAD üyelerinin gen ifadelerinde anlamlı artışlar olduğunu önermektedir.Endoplasmic reticulum (ER) serves as a complex center that mediates the synthesis one-third of all membrane and secretory proteins in eukaryotic cells to achieve their proper conformation.“Quality control mechanism” organized in the ER blocks exit of proteins that cannot reach their final conformation from ER and therefore it protects cells against proteotoxic effects by targeting these unwanted proteins to the proteasome via ER-associated protein degradation pathway (ERAD). It is also known that this mechanism also regulated basal level of many proteins with critical cellular roles such as HMG-CoA reductase and cytochrome p450 monooxygenase. Genotoxic effects, mutations, and chemical agents impair the activity of ERAD causing many pathophysiological consequences in cells. ERAD has been associated with several diseases such as Syndromes with multiple organ failure like IBMPFD, diabetes mellitus, retinitis pigmentosa or neurodegenerative disorders such as Huntington's, Alzheimer's, Parkinson’s diseases, and many cancer types have been associated with ERAD. To determine the relationship between ERAD and cancer, the most common disease of today is especially important. Due to the fact that prostate cancer is among the most common cancer types following skin cancer among male subjects, it is center of interest for many research groups. Therefore, the number of studies on the relationship between many cellular molecular mechanisms and prostate cancer has been increased with every passing day. As a part of a project aiming elucidation of the relationship between prostate carcinogenesis and ERAD members, we have evaluated the gene expression profile of several ERAD genes involved in different steps; namely Hrd1, gp78, p97/VCP, SVIP, Derlin1, Ufd1, Npl4, OS9 and UFD2A, and their association with prostate cancer in a total of 48 individuals with 9 healthy and 39 prostate cancers. Our findings suggest that there is a significant increase in gene expression of ERAD members and is correlated with prostate carcinogenesis

UBIQUITIN LIGASES AS TARGETS FOR DRUG DISCOVERY

WOS: 00026408950012

Introduction to Molecular Biology Related to Electrochemical DNA-Based Biosensors

WOS: 00031269770001