Loss of HRD1-Mediated Protein Degradation Causes Amyloid Precursor Protein Accumulation and Amyloid-β Generation

Kaneko, Masayuki; Koike, Hiroshi; Saito, Ryo; Kitamura, Yoshihisa; Okuma, Yasunobu; Nomura, Yasuyuki

doi:10.1523/jneurosci.2422-09.2010

Cited by 161 publications

(130 citation statements)

References 39 publications

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“…The two mammalian orthologs of yeast Hrd1p, HRD1 (Synoviolin) and gp78 (AMFR), have distinct substrate specificities, exemplifying the increased complexity of mammalian ERAD (6,7). HRD1 is implicated in the pathogenesis of rheumatoid arthritis (10), and reported substrates include α1-antitrypsin variants (11) and amyloid precursor protein (12). Three E2 ubiquitin-conjugating enzymes function in mammalian ERAD: UBE2J1 and UBE2J2 (yeast Ubc6p orthologs) and UBE2G2 (yeast Ubc7p ortholog) (7,8,13).…”

mentioning

confidence: 99%

HRD1 and UBE2J1 target misfolded MHC class I heavy chains for endoplasmic reticulum-associated degradation

Burr

Cano

Svobodova

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

120

118

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The assembly of MHC class I molecules is governed by stringent endoplasmic reticulum (ER) quality control mechanisms. MHC class I heavy chains that fail to achieve their native conformation in complex with β2-microglobulin (β2m) and peptide are targeted for ER-associated degradation. This requires ubiquitination of the MHC class I heavy chain and its dislocation from the ER to the cytosol for proteasome-mediated degradation, although the cellular machinery involved in this process is unknown. Using an siRNA functional screen in β2m-depleted cells, we identify an essential role for the E3 ligase HRD1 (Synoviolin) together with the E2 ubiquitin-conjugating enzyme UBE2J1 in the ubiquitination and dislocation of misfolded MHC class I heavy chains. HRD1 is also required for the ubiquitination and degradation of the naturally occurring hemochromatosisassociated HFE-C282Y mutant, which is unable to bind β2m. In the absence of HRD1, misfolded HLA-B27 accumulated in cells with a normal MHC class I assembly pathway, and HRD1 depletion prevented the appearance of low levels of cytosolic unfolded MHC I heavy chains. HRD1 and UBE2J1 associate in a complex together with non-β2m bound MHC class I heavy chains, Derlin 1, and p97 and discriminate misfolded MHC class I from conformational MHC Iβ2m-peptide heterotrimers. Together these data support a physiological role for HRD1 and UBE2J1 in the homeostatic regulation of MHC class I assembly and expression.

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confidence: 99%

HRD1 and UBE2J1 target misfolded MHC class I heavy chains for endoplasmic reticulum-associated degradation

Burr

Cano

Svobodova

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

120

118

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“…1c), whereas soluble HRD1 levels were not correlated with soluble SEL1L levels. 13) We speculate the reason for this inconsistency is a difference in protein content. In other words, HRD1 protein content might be much less than SEL1L.…”

Section: Discussionmentioning

confidence: 95%

“…13) To determine the cause of the decrease in HRD1 protein level in the NP-40 detergent-soluble fraction, we investigated protein levels in the detergent-insoluble fraction of the cerebral cortex of control and AD patients. In contrast to the observation of the detergent-soluble fraction, HRD1 protein levels significantly increased in the insoluble fraction (Figs.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, we found that HRD1 protein levels were significantly low in the NP-40 detergent-soluble fraction of the cerebral cortex of AD patients, and that low level of HRD1 protein in AD patients did not result from a decrease in mRNA expression but from a decrease in its protein levels. 13) Moreover, the decrease in the protein levels of HRD1 highly correlated with Aβ production. 14) However, it was not clear why HRD1 protein levels were reduced in the cerebral cortex.…”

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confidence: 94%

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Possible Involvement of Ubiquitin Ligase HRD1 Insolubilization in Amyloid .BETA. Generation

Kaneko

Saito

Okuma

et al. 2012

Biological & Pharmaceutical Bulletin

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Endoplasmic reticulum (ER)-associated degradation (ERAD) selectively retro-transports and degrades unfolded proteins accumulated in the ER. We have demonstrated that the ubiquitin ligase HRD1 involved in ERAD was significantly decreased in the cerebral cortex of Alzheimer's disease patients. Furthermore, the HRD1 level was negatively correlated with amyloid β (Aβ) production levels. Here we found that the HRD1 protein level decrease was due to its insolubilization. Moreover, these protein levels extracted from detergent insoluble fraction were positively correlated with those of SEL1L and Aβs (Aβ40 and Aβ42). Thus, the insolubilization-induced decrease in the HRD1 and SEL1L levels might involve in Aβ generation.Key words Alzheimer's disease; amyloid β; HRD1; endoplasmic reticulum stress; SEL1L; insolubilization Alzheimer's disease (AD) is a progressive neurodegenerative disease of unknown etiology. Accumulation of amyloid β (Aβ) plaques and neurofibrillary tangles are the well-known neuropathological hallmarks of AD.1) The toxic Aβ peptides, Aβ40 and Aβ42, are generated from amyloid precursor protein (APP) via sequential proteolytic cleavages by β-secretase (BACE1) and γ-secretase complexes.2) APP is a type-I transmembrane glycoprotein, which is folded and N-glycosylated in the endoplasmic reticulum (ER) and is subsequently transported to the Golgi complex for further maturation.The ER is involved in the following several cellular functions: (i) membrane and secretory protein folding, posttranslational modification, and transport to the Golgi complex; (ii) maintenance of intracellular calcium homeostasis; (iii) synthesis of lipids and sterols; and (iv) regulation of cellular survival through the unfolded protein response (UPR) transducers, such as IRE1, ATF6, and PERK. Impairment of these processes causes an accumulation of unfolded proteins in the ER lumen, which is termed ER stress. ER stress activates the UPR pathways such as translational arrest, induction of ER chaperone, and ER-associated degradation (ERAD).3) ERAD pathways act as a defense mechanism against ER stress. In this pathway, ERAD targets are selected by a protein quality control mechanism within the ER lumen, subsequently removed by retrograde transport from the ER to the cytosol, and finally degraded by the ubiquitin-proteasome system. 4,5) Recent studies have shown an involvement of ER stress and dysfunction of ERAD pathway in AD. 6,7) In previous studies, we identified and characterized a human homolog of yeast Hrd1p/Der3p (HRD1) and Hrd3p (SEL1L). HRD1 has an E3 ubiquitin ligase activity and it colocalizes and forms a complex with its stabilizing factor SEL1L in the cerebral nerve. Furthermore, HRD1 is expressed as a result of ER stress and protects against ER stress-induced apoptosis. 5,[8][9][10][11][12] We recently found that HRD1 promoted the ubiquitination and degradation of APP in ERAD pathway, resulting in decreased Aβ production. On the other hand, suppression of HRD1 expression caused an accumulation of APP and an increase in Aβ lev...

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“…Furthermore, sXBP1 was shown to reduce the level of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), which plays a key role in Aβ production (47). The reduction of BACE1 level is mediated through the ubiquitin-ligase 3-hydroxy-3-methylglutaryl-coenzyme A reductase degradation 1 (HRD1) (47) which is also involved in APP degradation and the subsequent reduction in Aβ production (48). Moreover, sXBP1 enhances memory formation possibly by increasing the production of brainderived neurotrophic factor (BDNF) in the CNS (49).…”

Section: Xbp1 and Neurodegenerative Diseasesmentioning

confidence: 99%

Link between endoplasmic reticulum stress and autophagy in neurodegenerative diseases

Hosoi¹,

Nomura²,

Tanaka³

et al. 2017

Endoplasmic Reticulum Stress in Diseases

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Increasing evidence suggests that endoplasmic reticulum (ER) stress and autophagy play an important role in regulating brain function. ER stress activates three major branches of the unfolded protein response (UPR) pathways, namely inositol-requiring enzyme-1 (IRE1), double stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK) and activating transcription factor 6 (ATF6)-mediated pathways. Recent studies have suggested that these UPR signals may be linked to autophagy. In this review article, we summarize recent evidence and discuss a possible link between ER stress and autophagy with regard to neurodegenerative diseases. Furthermore, possible pharmacological strategies targeting UPR and autophagy are discussed.

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Loss of HRD1-Mediated Protein Degradation Causes Amyloid Precursor Protein Accumulation and Amyloid-β Generation

Cited by 161 publications

References 39 publications

HRD1 and UBE2J1 target misfolded MHC class I heavy chains for endoplasmic reticulum-associated degradation

HRD1 and UBE2J1 target misfolded MHC class I heavy chains for endoplasmic reticulum-associated degradation

Possible Involvement of Ubiquitin Ligase HRD1 Insolubilization in Amyloid .BETA. Generation

Link between endoplasmic reticulum stress and autophagy in neurodegenerative diseases

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