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Autophagic Removal of Farnesylated Carboxy-Terminal Lamin Peptides

The mammalian nuclear lamina proteins—prelamin A- and B-type lamins—are post-translationally modified by farnesylation, endoproteolysis, and carboxymethylation at a carboxy-terminal CAAX (C, cysteine; a, aliphatic amino acid; X, any amino acid) motif. However, prelamin A processing into mature lamin...

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Autores principales: Lu, Xiang, Djabali, Karima
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946110/
https://www.ncbi.nlm.nih.gov/pubmed/29690642
http://dx.doi.org/10.3390/cells7040033
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author Lu, Xiang
Djabali, Karima
author_facet Lu, Xiang
Djabali, Karima
author_sort Lu, Xiang
collection PubMed
description The mammalian nuclear lamina proteins—prelamin A- and B-type lamins—are post-translationally modified by farnesylation, endoproteolysis, and carboxymethylation at a carboxy-terminal CAAX (C, cysteine; a, aliphatic amino acid; X, any amino acid) motif. However, prelamin A processing into mature lamin A is a unique process because it results in the production of farnesylated and carboxymethylated peptides. In cells from patients with Hutchinson–Gilford progeria syndrome, the mutant prelamin A protein, progerin, cannot release its prenylated carboxyl-terminal moiety and therefore remains permanently associated with the nuclear envelope (NE), causing severe nuclear alterations and a dysmorphic morphology. To obtain a better understanding of the abnormal interaction and retention of progerin in the NE, we analyzed the spatiotemporal distribution of the EGFP fusion proteins with or without a nuclear localization signal (NLS) and a functional CAAX motif in HeLa cells transfected with a series of plasmids that encode the carboxy-terminal ends of progerin and prelamin A. The farnesylated carboxy-terminal fusion peptides bind to the NE and induce the formation of abnormally shaped nuclei. In contrast, the unfarnesylated counterparts exhibit a diffuse localization in the nucleoplasm, without obvious NE deformation. High levels of farnesylated prelamin A and progerin carboxy-terminal peptides induce nucleophagic degradation of the toxic protein, including several nuclear components and chromatin. However, SUN1, a constituent of the linker of nucleoskeleton and cytoskeleton (LINC) complex, is excluded from these autophagic NE protrusions. Thus, nucleophagy requires NE flexibility, as indicated by SUN1 delocalization from the elongated NE–autophagosome complex.
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spelling pubmed-59461102018-05-15 Autophagic Removal of Farnesylated Carboxy-Terminal Lamin Peptides Lu, Xiang Djabali, Karima Cells Article The mammalian nuclear lamina proteins—prelamin A- and B-type lamins—are post-translationally modified by farnesylation, endoproteolysis, and carboxymethylation at a carboxy-terminal CAAX (C, cysteine; a, aliphatic amino acid; X, any amino acid) motif. However, prelamin A processing into mature lamin A is a unique process because it results in the production of farnesylated and carboxymethylated peptides. In cells from patients with Hutchinson–Gilford progeria syndrome, the mutant prelamin A protein, progerin, cannot release its prenylated carboxyl-terminal moiety and therefore remains permanently associated with the nuclear envelope (NE), causing severe nuclear alterations and a dysmorphic morphology. To obtain a better understanding of the abnormal interaction and retention of progerin in the NE, we analyzed the spatiotemporal distribution of the EGFP fusion proteins with or without a nuclear localization signal (NLS) and a functional CAAX motif in HeLa cells transfected with a series of plasmids that encode the carboxy-terminal ends of progerin and prelamin A. The farnesylated carboxy-terminal fusion peptides bind to the NE and induce the formation of abnormally shaped nuclei. In contrast, the unfarnesylated counterparts exhibit a diffuse localization in the nucleoplasm, without obvious NE deformation. High levels of farnesylated prelamin A and progerin carboxy-terminal peptides induce nucleophagic degradation of the toxic protein, including several nuclear components and chromatin. However, SUN1, a constituent of the linker of nucleoskeleton and cytoskeleton (LINC) complex, is excluded from these autophagic NE protrusions. Thus, nucleophagy requires NE flexibility, as indicated by SUN1 delocalization from the elongated NE–autophagosome complex. MDPI 2018-04-23 /pmc/articles/PMC5946110/ /pubmed/29690642 http://dx.doi.org/10.3390/cells7040033 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lu, Xiang
Djabali, Karima
Autophagic Removal of Farnesylated Carboxy-Terminal Lamin Peptides
title Autophagic Removal of Farnesylated Carboxy-Terminal Lamin Peptides
title_full Autophagic Removal of Farnesylated Carboxy-Terminal Lamin Peptides
title_fullStr Autophagic Removal of Farnesylated Carboxy-Terminal Lamin Peptides
title_full_unstemmed Autophagic Removal of Farnesylated Carboxy-Terminal Lamin Peptides
title_short Autophagic Removal of Farnesylated Carboxy-Terminal Lamin Peptides
title_sort autophagic removal of farnesylated carboxy-terminal lamin peptides
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946110/
https://www.ncbi.nlm.nih.gov/pubmed/29690642
http://dx.doi.org/10.3390/cells7040033
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