Protein feature analysis of heat shock induced ubiquitination sites reveals preferential modification site localization

Kuechler, Erich R.; Rose, Amalia; Bolten, Marcel; Madero, Angel M.; Kammoonah, Shaima; Colborne, Shane; Gsponer, Joerg; Morin, Gregg B.; Mayor, Thibault

doi:10.1016/j.jprot.2021.104182

Cited by 3 publications

(2 citation statements)

References 66 publications

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“…PTMs play a crucial role in governing protein functions by significantly affecting the structure and dynamics of proteins (Mann and Jensen 2003). It has been reported that heat stress-induced ubiquitination tends to accumulate within structured domains (Kuechler et al 2021). Ubiquitination is also implicated in promoting inclusions by sequestering misfolded proteins.…”

Section: Discussionmentioning

confidence: 99%

Elucidation of Site-Specific Ubiquitination on Chaperones in Response to Mutant Huntingtin

Panda,

Sarohi,

Basak

et al. 2023

Cell Mol Neurobiol

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Huntington's disease (HD) is one of the prominent neurodegenerative diseases, characterized by the progressive decline of neuronal function, due to the accumulation and aggregation of misfolded proteins. Pathological progression of HD is hallmarked by the aberrant aggregation of the huntingtin protein (HTT) and subsequent neurotoxicity. Molecular chaperones (heat shock proteins, HSPs) play a pivotal role in maintaining proteostasis by facilitating protein refolding, degradation, or sequestration to limit the accumulation of misfolded proteins during neurotoxicity. However, the role of posttranslational modifications such as ubiquitination among HSPs during HD is less known. In this study, we aimed to elucidate HSPs ubiquitin code in the context of HD pathogenesis. In a comprehensive proteomic analysis, we identified site-specific ubiquitination events in HSPs associated with HTT in HD-affected brain regions. To assess the impact of ubiquitination on HSPs during HD, we quantified the abundance of ubiquitinated lysine sites in both the rat cortex/striatum and in the mice primary cortical neurons. Strikingly, we observed highly tissue-specific alterations in the relative ubiquitination levels of HSPs under HD conditions, emphasizing the importance of spatial perturbed post-translational modifications (PTMs) in shaping disease pathology. These ubiquitination events, combined with other PTMs on HSPs, are likely to influence the phase-transitions of HTT. In conclusion, our study uncovered differential site-specific ubiquitination of molecular chaperones and offers a comprehensive view of the intricate relationship between protein aggregation, and PTMs in the context of Huntington's disease.

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Section: Discussionmentioning

confidence: 99%

Elucidation of Site-Specific Ubiquitination on Chaperones in Response to Mutant Huntingtin

Panda,

Sarohi,

Basak

et al. 2023

Cell Mol Neurobiol

View full text Add to dashboard Cite

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“…Under stress conditions, such as high temperature, cells must rapidly adapt by increasing their folding capacity to eliminate abnormal proteins. Proteostasis in this way requires a balance of protein synthesis, folding, and degradation [5]. In S. cerevisiae, Benet et al [6] observed that cellular gene translation capacity and protein degradation rates increased in response to changes in external temperature.…”

Section: Introductionmentioning

confidence: 99%

The Protein Response of Salt-Tolerant Zygosaccharomyces rouxii to High-Temperature Stress during the Lag Phase

Hu,

Xiao,

Yao

et al. 2024

JoF

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Zygosaccharomyces rouxii used in soy sauce brewing is an osmotolerant and halotolerant yeast, but it is not tolerant to high temperatures and the underlying mechanisms remain poorly understood. Using a synthetic medium containing only Pro as a nitrogen source, the response of Z. rouxii in protein level to high-temperature stress (40 °C, HTS) during the lag phase was investigated. Within the first two h, the total intracellular protein concentration was significantly decreased from 220.99 ± 6.58 μg/mg DCW to 152.63 ± 10.49 μg/mg DCW. The analysis of the amino acid composition of the total protein through vacuum proteolysis technology and HPLC showed that new amino acids (Thr, Tyr, Ser, and His) were added to newborn protein over time during the lag phase under HTS. The nutritional conditions used in this study determined that the main source of amino acid supply for protein synthesis was through amino acid biosynthesis and ubiquitination-mediated protein degradation. Differential expression analysis of the amino acid biosynthesis-related genes in the transcriptome showed that most genes were upregulated under HTS, excluding ARO8, which was consistently repressed during the lag phase. RT-qPCR results showed that high-temperature stress significantly increased the upregulation of proteolysis genes, especially PSH1 (E3 ubiquitin ligase) by 13.23 ± 1.44 fold (p < 0.0001) within 4 h. Overall, these results indicated that Z. rouxii adapt to prolonged high temperatures stress by altering its basal protein composition. This protein renewal was related to the regulation of proteolysis and the biosynthesis of amino acids.

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Elucidation of chaperone ubiquitin code in response to Huntingtin aggregation

Panda,

Sarohi,

Basak

et al. 2023

Preprint

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Huntington's disease (HD) is one of the prominent neurodegenerative diseases, characterized by the progressive decline of neuronal function, due to the accumulation and aggregation of misfolded proteins. Pathological progression of HD is hallmarked by the aberrant aggregation of the huntingtin protein (HTT) and subsequent neurotoxicity. Molecular chaperones (heat shock proteins, HSPs) play a pivotal role in maintaining proteostasis by facilitating protein refolding, degradation, or sequestration to limit the accumulation of misfolded proteins during neurotoxicity. However, the role of post-translational modifications such as ubiquitination among HSPs during HD is less known. In this study, we aimed to elucidate HSPs ubiquitin code in the context of HD pathogenesis. In a comprehensive proteomic analysis, we identified site-specific ubiquitination events in HSPs associated with HTT in HD-affected brain regions. To assess the impact of ubiquitination on HSPs during HD, we quantified the abundance of ubiquitinated lysine sites in both the rat cortex/striatum and in the mice primary cortical neurons. Strikingly, we observed highly tissue-specific alterations in the relative ubiquitination levels of HSPs under HD conditions, emphasizing the importance of spatial perturbed post-translational modifications (PTMs) in shaping disease pathology. These ubiquitination events, combined with other PTMs on HSPs, are likely to influence the phase-transitions of HTT. In conclusion, our study uncovered differential site-specific ubiquitination of molecular chaperones and offers a comprehensive view of the intricate relationship between protein aggregation, and PTMs in the context of Huntington's disease.

show abstract

Protein feature analysis of heat shock induced ubiquitination sites reveals preferential modification site localization

Cited by 3 publications

References 66 publications

Elucidation of Site-Specific Ubiquitination on Chaperones in Response to Mutant Huntingtin

Elucidation of Site-Specific Ubiquitination on Chaperones in Response to Mutant Huntingtin

The Protein Response of Salt-Tolerant Zygosaccharomyces rouxii to High-Temperature Stress during the Lag Phase

Elucidation of chaperone ubiquitin code in response to Huntingtin aggregation

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