title: The endoplasmic reticulum (ER)-associated degradation system regulates aggregation and degradation of mutant neuroserpin.
abstract: Familial encephalopathy with neuroserpin inclusion bodies is a neurodegenerative disorder characterized by the accumulation of neuroserpin polymers in the endoplasmic reticulum (ER) of cortical and subcortical neurons in the CNS because of neuroserpin point mutations. ER-associated degradation (ERAD) is involved in mutant neuroserpin degradation. In this study, we demonstrate that two ER-associated E3 ligases, Hrd1 and gp78, are involved in the ubiquitination and degradation of mutant neuroserpin. Overexpression of Hrd1 and gp78 decreases the mutant neuroserpin protein level, whereas Hrd1 and gp78 knockdown increases mutant neuroserpin stability. Moreover, ERAD impairment by mutant valosin-containing protein increases the mutant neuroserpin protein level and aggregate formation. Thus, these findings identify mutant neuroserpin as an ERAD target and show that Hrd1 and gp78 mediate mutant neuroserpin turnover through the ERAD pathway.
authors.affiliation: FroLaboratory of Molecular Neuropathology, School of Life Sciences, University of Science and Technology of China, Chinese Academy of Sciences, Hefei, Anhui 230027, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Ying
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Wang
authors.forename: Huadong
authors.initials: H
authors.lastname: Fan
authors.forename: Guanghui
authors.initials: G
authors.lastname: Wang
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D004831:Epilepsies, Myoclonic / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D009154:Mutation; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D060285:Receptors, Autocrine Motility Factor; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism*; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D000074405:Valosin Containing Protein; D000097522:Neuroserpin
chemical_list: D000251:Adenosine Triphosphatases; D018797:Cell Cycle Proteins; D009479:Neuropeptides; D060285:Receptors, Autocrine Motility Factor; D018121:Receptors, Cytokine; D015843:Serpins; D044767:Ubiquitin-Protein Ligases; D000074405:Valosin Containing Protein; D000097522:Neuroserpin; C555000:AMFR protein, human; C555002:Amfr protein, mouse; C482345:SYVN1 protein, human; C000614178:VCP protein, human; C000614179:Vcp protein, mouse