Misfolded proteins of the endoplasmic reticulum (ER) are discarded by a conserved process, called ER-associated protein degradation (ERAD). ERAD substrates are retro-translocated into the cytosol, polyubiquitinated, extracted from the ER …

2014年2月7日 · Deubiquitinating enzymes (DUBs) regulate various cellular processes ranging from protein degradation to cellular signaling. USP19, the only DUB containing a carboxyl-terminal transmembrane domain, was proposed to function in endoplasmic reticulum-associated degradation (ERAD). Here we characterize the function and regulation of USP19.

Distinct endoplasmic reticulum-associated degradation (ERAD) pathways. Three main ERAD pathways in yeast are classified based on substrates and the components that are involved in their degradation. ERAD-L degrades membrane integrated or soluble proteins with misfolded domains in the ER lumen, marked with (L).

2021年8月1日 · DUBs function as modulators in a variety of neurodegenerative diseases. DUBs regulate toxic proteins inducing neurodegenerative diseases via proteasome signaling, mitophagy, autophagy, and ERAD. DUB small molecule inhibitors affect the targeted toxic proteins related to neurodegenerative diseases via decomposition mechanism.

Surprisingly, recent studies have revealed an equally important function for deubiquitinases (DUBs), enzymes that disassemble ubiquitin chains, in ERAD. Intriguingly, many ERAD specific DUBs are physically associated with the retrotranslocation-driving ATPase p97.

2020年10月21日 · The right panel diagrams the function of the Otu1 DUB in ER-associated degradation (ERAD) of substrates that are polyubiquitinated by Hrd1. The Cdc48 ATPase (black shape) is recruited to the ER membrane and uses ATP hydrolysis to pull the polypeptide substrate out of the membrane.

Ubiquitination in ERAD is also controlled by the opposing effect of deubiquitinases (DUB) that remove ubiquitin chains conjugated with ERAD substrates. DUBs were found to be in close association with p97/VCP and 26S proteasome, which suggests their role in substrate dislocation and proteasomal function.

2014年9月11日 · Recent experiments have also implicated deubiquitinating enzymes (DUBs) in ERAD (for review, see Liu and Ye, 2012). Several DUBs associate with Cdc48p or its mammalian homolog p97, and the overexpression of dominant-negative forms blocks ERAD in mammalian cells. However, it remains unclear how DUBs participate in ERAD.

2019年2月5日 · 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.

泛素一蛋白酶体途径 （ubiquitin-proteasome pathway）是细胞内一个重要的蛋白质降解调节系统。 通过对底物蛋白的多聚泛素化并经蛋白酶体降解，可以影响或调节多种细胞活动，包括：基因转录、细胞周期调节、免疫反应、细胞受体功能及肿瘤生长、炎症过程等。 该途径也是一种动态的蛋白质双向修饰调控系统，在体内由 泛素连接酶系统 （E1-E2-E3）对底物进行泛素化修饰，去泛素化酶（DUB）家族负责通过水解泛素羧基末端的酯键、肽键或异肽键，将泛素分子特异性的从 …