A critical role of Hrd1 in the regulation of optineurin degradation and aggresome formation.
Mutations in optineurin (OPTN) are associated with several human disorders including amyotrophic lateral sclerosis (ALS) and primary open-angle glaucoma (POAG). OPTN is known to be a multifunctional autophagy receptor that plays important roles in NF-κB signaling, vesicle trafficking, maintenance of the Golgi apparatus and autophagy. Given that a loss of neurons and an abnormal aggregation of disease proteins are two key features of neurodegenerative diseases, protein quality control systems are considered to be tightly associated with neurodegeneration. In this study, we investigated the involvement of the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway, two major intracellular protein quality control systems, in the regulation of wild-type (WT) OPTN, ALS-linked mutant E478G OPTN and POAG-linked mutant E50K OPTN. Our data revealed that the UPS, not the autophagy-lysosome pathway, is the major system for degradation and aggregation of OPTN. Moreover, we found that Hrd1, an E3 ubiquitin ligase, could play an important role in the protein quality control of OPTN. Our results demonstrated that overexpression of Hrd1 increased the proteasomal degradation and microtubule-dependent aggresome formation of OPTN in the microtubular organizing center, whereas knockdown of Hrd1 stabilized OPTN and inhibited aggresome formation of OPTN.
Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China.|Department of Pathophysiology, Nantong University School of Medicine, Nantong, Jiangsu 226001, China.
Jiahui
J
Mao
Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China.
Qin
Q
Xia
Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China.
Chunfeng
C
Liu
Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China.|Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China.
Zheng
Z
Ying
Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China.
Hongfeng
H
Wang
Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China.
Guanghui
G
Wang
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics; D001343:Autophagy / Q000235:genetics; D018797:Cell Cycle Proteins; D005902:Glaucoma, Open-Angle / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D026901:Membrane Transport Proteins; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D015398:Signal Transduction; D035582:Transcription Factor TFIIIA / Q000378:metabolism*; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
D018797:Cell Cycle Proteins; D026901:Membrane Transport Proteins; D016328:NF-kappa B; C409460:OPTN protein, human; D035582:Transcription Factor TFIIIA; D025801:Ubiquitin; C482345:SYVN1 protein, human; D044767:Ubiquitin-Protein Ligases