SOD1 deficiency decreases proteasomal function, leading to the accumulation of ubiquitinated proteins in erythrocytes

Homma, Takujiro; Kurahashi, Takashi; Lee, Jae Yong; Kang, Eun Sil; Fujii, Junichi

doi:10.1016/j.abb.2015.07.023

Cited by 16 publications

(7 citation statements)

References 46 publications

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“…Mutation of the mouse Sod1 gene (knockout) decreases the number of erythrocytes and quantity of peripheral blood red blood cells22. A recent study reported that oxidative-stress triggers dysfunction of the proteasomal system and accelerates the accumulation of damaged proteins, leading to a shortened lifespan of RBCs and, hence, anemia in Sod1-deficient mice23. In the present study SOD1 was found to be highly negatively correlated with HCT and RBC and exhibited a cis-eQTL.…”

Section: Discussionsupporting

confidence: 57%

Genetically regulated hepatic transcripts and pathways orchestrate haematological, biochemical and body composition traits

Ponsuksili

Trakooljul

Hadlich

et al. 2016

Sci Rep

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The liver is the central metabolic organ and exhibits fundamental functions in haematological traits. Hepatic expression, haematological, plasma biochemical, and body composition traits were assessed in a porcine model (n = 297) to establish tissue-specific genetic variations that influence the function of immune-metabolism-correlated expression networks. At FDR (false discovery rate) <1%, more than 3,600 transcripts were jointly correlated (r = |0.22–0.48|) with the traits. Functional enrichment analysis demonstrated common links of metabolic and immune traits. To understand how immune and metabolic traits are affected via genetic regulation of gene expression, eQTLs were assessed. 20517 significant (FDR < 5%) eQTLs for 1401 transcripts were identified, among which 443 transcripts were associated with at least one of the examined traits and had cis-eQTL (such as ACO1 (6.52 × 10−7) and SOD1 (6.41 × 10−30). The present study establishes a comprehensive view of hepatic gene activity which links together metabolic and immune traits in a porcine model for medical research.

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Section: Discussionsupporting

confidence: 57%

Genetically regulated hepatic transcripts and pathways orchestrate haematological, biochemical and body composition traits

Ponsuksili

Trakooljul

Hadlich

et al. 2016

Sci Rep

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“…Previous studies have indicated that ROS induce the accumulation of ubiquitinated proteins and dysfunctional proteasomal activity [37,38]. In the present study, the proteasomal activities, cell viabilities, and UPS-related proteins UBE1, PSMA7, and UCHL1 were increased in 72-h D -gal-treated primary cells but decreased in 5-day D -gal-treated primary cells (Fig.…”

Section: Discussionsupporting

confidence: 58%

Role of the Ubiquitin C-Terminal Hydrolase L1-Modulated Ubiquitin Proteasome System in Auditory Cortex Senescence

Zhang

Huang²,

Zhao³

et al. 2017

ORL

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Background/Aims: According to recent studies, central auditory impairments are closely related to neurodegenerative diseases. However, the mechanism of central presbycusis remains unclear. Ubiquitin C-terminal hydrolase L1 (UCHL1) is important in maintaining proteasomal activity; however, the detailed mechanism has not yet been fully elucidated. This study aims to investigate the molecular alterations involved in UCHL1 regulation during auditory cortex aging. Methods:D-Galactose (D-gal) induces oxidative stress and senescence in the auditory cortex, as reported in our previous studies. Primary auditory cortex cells were treated with D-gal for 72 h or 5 days. The proteins related to the ubiquitin proteasome system (UPS) and proteasomal activities were evaluated. UCHL1 was overexpressed, and the effects of UCHL1 on the UPS and proteasomal activity were analyzed. Results: Proteasomal activity was elevated at 72 h and decreased at 5 days in D-gal-treated primary auditory cortex cells. We also found that overexpression of UCHL1 increased the UPS-related proteins UBE1, PSMA7, ubiquitinated proteins, and monoubiquitin, and proteasomal activity. Conclusion: The results suggest that UCHL1 may modify the aging process in the auditory cortex by regulating UPS- related proteins.

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“…It has been shown that moderately HNE-modified proteins are preferentially degraded by proteasomes, but that proteins that are more extensively modified undergo aggregation, which can inhibit proteasome function [42]. We recently reported on a decreased proteasomal function and increased accumulation of ubiquitinated proteins in SOD1-KO RBCs [16]. A significant decline in proteasome activity upon severe oxidative stress has also been reported in cultured cells [43,44].…”

Section: Rosmentioning

confidence: 90%

“…Whereas ROS produced via the autoxidation of hemoglobin are involved in the hyperoxidation of PRDX, the removal of PRDX-SO2/3 by proteasomal degradation appears to give rise to cyclic changes in PRDX-SO2/3 in RBCs, even under cultured conditions [47]. In the case of SOD1-KO mice, however, PRDX-SO2/3 in RBCs accumulates markedly with no associated cyclic changes [48], which can be rationally explained by the dysfunction of the proteasomal system by elevated ROS [16]. It is therefore likely that oxidative stress disturbs proteasome activity and, in turn, triggers the accumulation of both ubiquitinated proteins and non-ubiquitinated oxidized proteins, leading to the destruction of RBCs.…”

Section: Rosmentioning

confidence: 99%

“…Sustained oxidative stress accelerates the production of damaged proteins, which eventually exceeds the capacity for proteasomal removal, leading to their accumulation in the cells [14,15]. We recently reported that the catalytic activities of proteasomes decrease due to increased levels of ROS, leading to the accumulation of ubiquitinated proteins in SOD1-KO RBCs [16]. Thus, oxidized proteins are not eliminated by proteasomes but accumulate, which triggers cellular dysfunction, premature aging, and, ultimately, the destruction of RBCs.…”

Section: Introductionmentioning

confidence: 99%

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Oxidative Stress Caused by an SOD1 Deficiency Triggers the Accumulation of Oxidatively Modified Carbonic Anhydrase II in Erythrocytes

Homma

Fujii

2018

ROS

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Red blood cells (RBCs) are continuously exposed to reactive oxygen species (ROS) that are largely produced from intrinsic sources such as the oxidation of hemoglobin. Since superoxide dismutase 1 (SOD1) is the sole superoxide-scavenging enzyme in RBCs, a deficiency leads to the development of hemolytic anemia in mice, suggesting that the underlying mechanism involves a massive, oxidative stressinduced destruction of RBCs. We recently reported a decreased proteasomal function and the accumulation of ubiquitinated proteins in RBCs in SOD1-knockout (KO) mice. Because proteasomes are responsible for the degradation of both ubiquitinated proteins and oxidatively-modified (oxidized) proteins without ubiquitination, their malfunction results in the accumulation of these proteins. In the current study, we examined the issue of how elevated ROS are involved in the destruction of RBCs and the onset of anemia from the point of view of the accumulation of oxidized proteins. The findings indicate that carbonic anhydrase II (CAII) was the major protein within RBCs that was oxidized and that high levels had accumulated in SOD1-KO RBCs. Using purified CAII, we demonstrated that oxidative modification decreased its enzymatic activity in a ROSdependent manner. In addition, the oxidized CAII molecules appeared to be degraded by proteasomes in RBCs. Based on these findings, we conclude that oxidative stress caused by an SOD1 deficiency disrupts the scavenging activity of proteasomes and accelerates the accumulation of oxidized CAII, leading to RBCs having a shortened life span.

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SOD1 deficiency decreases proteasomal function, leading to the accumulation of ubiquitinated proteins in erythrocytes

Cited by 16 publications

References 46 publications

Genetically regulated hepatic transcripts and pathways orchestrate haematological, biochemical and body composition traits

Genetically regulated hepatic transcripts and pathways orchestrate haematological, biochemical and body composition traits

Role of the Ubiquitin C-Terminal Hydrolase L1-Modulated Ubiquitin Proteasome System in Auditory Cortex Senescence

Oxidative Stress Caused by an SOD1 Deficiency Triggers the Accumulation of Oxidatively Modified Carbonic Anhydrase II in Erythrocytes

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