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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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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2018
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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. |
format | Online Article Text |
id | pubmed-5946110 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT luxiang autophagicremovaloffarnesylatedcarboxyterminallaminpeptides AT djabalikarima autophagicremovaloffarnesylatedcarboxyterminallaminpeptides |