The proteasome maturation protein POMP increases proteasome assembly and activity in psoriatic lesional skin

Zieba, Barbara A.; Henry, Laurent; Lacroix, Matthieu; Jèmaà, Mohamed; Lavabre‐Bertrand, Thierry; Meunier, Laurent; Coux, Olivier; Stoebner, Pierre‐Emmanuel

doi:10.1016/j.jdermsci.2017.04.009

Cited by 12 publications

(5 citation statements)

References 55 publications

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“…We believe that proteasome degradation is less important in the cells in which the protein is sequestered within KHGs since the proteasome is not able to access this pool. The study by Zieba et al, showing regulation of POMP expression during normal keratinocyte differentiation, is in agreement with this, indicating that proteasome functionality is the most pronounced at the early stages of this process, corresponding to basal and suprabasal epidermal layers 145 .…”

Section: Discussionsupporting

confidence: 79%

In silico analysis of the profilaggrin sequence indicates alterations in the stability, degradation route, and intracellular protein fate in filaggrin null mutation carriers

Paul

Szulc

Kobiela

et al. 2022

Preprint

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Background Loss of function mutation in FLG is the major genetic risk factor for atopic dermatitis (AD) and other allergic manifestations. Presently, little is known about the cellular turnover and stability of profilaggrin, the protein encoded by FLG. Since ubiquitination directly regulates the cellular fate of numerous proteins, their degradation and trafficking, this process could influence the concentration of filaggrin in the skin. Objective To determine the elements mediating the interaction of profilaggrin with the ubiquitin-proteasome system (i.e., degron motifs and ubiquitination sites), the features responsible for its stability, and the effect of nonsense and frameshift mutations on profilaggrin turnover. Methods The effect of proteasome inhibition on the expression of profilaggrin and processed products was assessed by immunoblotting. Wild-type profilaggrin sequence and its mutated variants were analysed in silico using the DEGRONOPEDIA and Clustal Omega tool. Results Proteasome inhibition stabilizes profilaggrin and its high molecular weight derivatives. In silico analysis of the sequence determined that profilaggrin contains 18 known degron motifs as well as multiple canonical and non-canonical ubiquitination-prone residues. FLG mutations generate products with increased stability scores, altered usage of the ubiquitination marks, and the frequent appearance of novel degrons, including those promoting C-terminus-mediated degradation routes. Conclusions The proteasome is involved in the turnover of profilaggrin, which contains multiple degrons and ubiquitination-prone residues. FLG mutations alter those key elements, affecting the degradation routes and the mutated products’ stability.

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Section: Discussionsupporting

confidence: 79%

In silico analysis of the profilaggrin sequence indicates alterations in the stability, degradation route, and intracellular protein fate in filaggrin null mutation carriers

Paul

Szulc

Kobiela

et al. 2022

Preprint

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“…Zieba and colleagues showed that the proteasome assembly chaperone POMP (proteasome maturation protein) was upregulated in psoriatic skin, resulting in an increase of proteasome levels and activities. Silencing POMP inhibited cell proliferation and differentiation, and promoted cell apoptosis via inhibition of the proteasome assembly [ 133 ]. E3 Ligase tripartite motif-containing 21 (Trim21) belongs to the Trim protein family with E3 ligase activity.…”

Section: Factors Regulating Psoriatic Keratinocytesmentioning

confidence: 99%

Advances in the pathogenesis of psoriasis: from keratinocyte perspective

et al. 2022

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Psoriasis is a complex long-lasting inflammatory skin disease with high prevalence and associated comorbidity. It is characterized by epidermal hyperplasia and dermal infiltration of immune cells. Here, we review the role of keratinocytes in the pathogenesis of psoriasis, focusing on factors relevant to genetics, cytokines and receptors, metabolism, cell signaling, transcription factors, non-coding RNAs, antimicrobial peptides, and proteins with other different functions. The critical role of keratinocytes in initiating and maintaining the inflammatory state suggests the great significance of targeting keratinocytes for the treatment of psoriasis.

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“…Importantly, such containment of the protein within KHGs prevents its access to the proteasome, which is not able to sample from those insoluble organelles. The importance of UPS-mediated control over profilaggrin is also supported by the biological pattern of the proteasome expression, which functions primarily in the undifferentiated keratinocytes, corresponding to basal and suprabasal epidermal layers ( Zieba et al, 2017 ); proteasome gets disassembled in the cells at the late stages of differentiation, which results from regulation of POMP expression.…”

Section: Discussionmentioning

confidence: 99%

In silico analysis of the profilaggrin sequence indicates alterations in the stability, degradation route, and intracellular protein fate in filaggrin null mutation carriers

Paul

Szulc

Kobiela

et al. 2023

Front. Mol. Biosci.

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Background: Loss of function mutation in FLG is the major genetic risk factor for atopic dermatitis (AD) and other allergic manifestations. Presently, little is known about the cellular turnover and stability of profilaggrin, the protein encoded by FLG. Since ubiquitination directly regulates the cellular fate of numerous proteins, their degradation and trafficking, this process could influence the concentration of filaggrin in the skin.Objective: To determine the elements mediating the interaction of profilaggrin with the ubiquitin-proteasome system (i.e., degron motifs and ubiquitination sites), the features responsible for its stability, and the effect of nonsense and frameshift mutations on profilaggrin turnover.Methods: The effect of inhibition of proteasome and deubiquitinases on the level and modifications of profilaggrin and processed products was assessed by immunoblotting. Wild-type profilaggrin sequence and its mutated variants were analysed in silico using the DEGRONOPEDIA and Clustal Omega tool.Results: Inhibition of proteasome and deubiquitinases stabilizes profilaggrin and its high molecular weight of presumably ubiquitinated derivatives. In silico analysis of the sequence determined that profilaggrin contains 18 known degron motifs as well as multiple canonical and non-canonical ubiquitination-prone residues. FLG mutations generate products with increased stability scores, altered usage of the ubiquitination marks, and the frequent appearance of novel degrons, including those promoting C-terminus-mediated degradation routes.Conclusion: The proteasome is involved in the turnover of profilaggrin, which contains multiple degrons and ubiquitination-prone residues. FLG mutations alter those key elements, affecting the degradation routes and the mutated products’ stability.

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The proteasome maturation protein POMP increases proteasome assembly and activity in psoriatic lesional skin

Abstract: Altogether these results establish a potential role for POMP and proteasome assembly in psoriasis pathogenesis.

Cited by 12 publications

References 55 publications

In silico analysis of the profilaggrin sequence indicates alterations in the stability, degradation route, and intracellular protein fate in filaggrin null mutation carriers

In silico analysis of the profilaggrin sequence indicates alterations in the stability, degradation route, and intracellular protein fate in filaggrin null mutation carriers

Advances in the pathogenesis of psoriasis: from keratinocyte perspective

In silico analysis of the profilaggrin sequence indicates alterations in the stability, degradation route, and intracellular protein fate in filaggrin null mutation carriers

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