![]() ![]() Substrates are then conjugated with polyubiquitin and retrotranslocated to cytosol by VCP–UFD1–NPL4 heterotrimer ( 13, 14). FAM8A1 increases the binding of HERP to HRD1, HERP facilitates Derlin1/2/3 recruitment and HRD1 oligomerization. In mammalians, substrates are recognized by OS9/XTP3-B and HRD1 complex receptor Sel1L and brought to HRD1 complex. Finally, the de-ubiquitinating enzyme (DUB) recruited and activated by the Cdc48p complex removes ubiquitin chains of Hrd1p ( 12). Subsequently, ATP hydrolysis by Cdc48p releases substrate from ER to cytosol for degradation. Substrates are then tagging with conjugation a polyubiquitin by Hrd1p and Hrd1p itself is also auto-ubiquitinated to recruit Cdc48p ATPase complex. ERAD-M/ERAD-C substrates are recognized by Doa10p complex. In yeasts, ERAD-L substrates are recognized by lectin Yos9 and Hrd1p complex receptor Hrd3p and then brought to the ER membrane to interact with Hrd1p. In mammalian cells, several E3 ligases participate in ERAD, including HRD1, glycoprotein 78 (gp78), membrane-associated RING finger protein 6 (MARCH6) ( 11). In yeasts, the best characterized ERAD pathways are mediated by the Hrd1p complex ((ERAD-L, ERAD-M, and ERAD-T) and Doa10p complex (ERAD-C, ERAD-M) ( 9, 10). In this review, we highlight recent advances in understanding the endogenous substrates, the physiological role of Sel1L-HRD1 ERAD in metabolism.ĮRAD substrates can be classified into four categories according to their degradation signal location: ERAD-L (lumen), ERAD-M (membrane), ERAD-C (cytosol) and ERAD-T (translocon). In recent studies, genetic deletion of several components of ERAD in specific cells of animals point out its indispensable physiological function. ![]() The suppressor/enhancer of lin-12-like (Sel1L)–HMG-CoA reductase degradation protein 1 (HRD1) complex is the most-conserved and best-characterized branch of ERAD. ERAD facilitates removal of misfolded proteins from the ER for ubiquitin- proteasomal degradation ( 4). Failure to degrade misfolded proteins activate UPR, which can upregulate the chaperones and ERAD components to increase protein fold capacity ( 8). ER stress is commonly found in metabolic diseases including T2DM, insulin resistance, and NAFLD ( 6).ĮRAD, unfolded protein response (UPR) and autophagy are the major protein quality and quantity control pathways to maintain ER homeostasis ( 7). Perturbation of ER homeostasis by cellular proteotoxicity, lipotoxicity and glucotoxicity can result in the accumulation of unfolded or misfolded proteins in the ER lumen and ER stress ( 4, 5). Lipid metabolism, protein balance, and calcium signaling processes controlled by the endoplasmic reticulum are closely related to metabolic disorders. The prevalence of overnutrition and sedentary lifestyles has led to global increase of metabolic disorders associated disease such as obesity, type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease ( 1, 2).Įndoplasmic reticulum is the major compartment of protein folding, calcium storage and nutrient sensing ( 3). Metazoans can coordinate different hormones, metabolic tissues and organs to adapt to metabolic changes. Changes in external nutritional conditions and lifestyles have led to evolve a series of mechanisms for metabolic adaption. Metabolism is a process of converting nutrients into energy to maintain cell growth and activity. ![]()
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