In silico analysis of the profilaggrin sequence indicates alterations in the stability, degradation route, and intracellular protein fate in filaggrin null mutation carriers
Loss of function mutation in 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 . Since ubiquitination directly regulates the cellular fate of nume...
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Published in | Frontiers in molecular biosciences Vol. 10; p. 1105678 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
Switzerland
Frontiers Media S.A
02.05.2023
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Subjects | |
Online Access | Get full text |
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Summary: | Loss of function mutation in
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
. 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.
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.
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
using the DEGRONOPEDIA and Clustal Omega tool.
Inhibition of proteasome and deubiquitinases stabilizes profilaggrin and its high molecular weight of presumably ubiquitinated derivatives.
analysis of the sequence determined that profilaggrin contains 18 known degron motifs as well as multiple canonical and non-canonical ubiquitination-prone residues.
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.
The proteasome is involved in the turnover of profilaggrin, which contains multiple degrons and ubiquitination-prone residues.
mutations alter those key elements, affecting the degradation routes and the mutated products' stability. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ORCID: Argho Aninda Paul, orcid.org/0000-0002-6229-0598; Natalia A. Szulc, orcid.org/0000-0002-2991-3634; Adrian Kobiela, orcid.org/0000-0002-8957-5366; Sara J. Brown, orcid.org/0000-0002-3232-5251; Wojciech Pokrzywa, orcid.org/0000-0002-5110-4462; Danuta Gutowska-Owsiak, orcid.org/0000-0003-4503-2279 Reviewed by: Bertrand Fabre, UMR5546 Laboratoire de Recherche en Sciences Vegetales (LRSV), France Edited by: Sumera Zaib, University of Central Punjab, Pakistan These authors share first authorship Laura Lynne Eggink, Susavion Biosciences, Inc., United States John Kenneth Hoober, Susavion Biosciences, Inc., United States |
ISSN: | 2296-889X 2296-889X |
DOI: | 10.3389/fmolb.2023.1105678 |