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Cells 2018, 7(4), 33; https://doi.org/10.3390/cells7040033

Autophagic Removal of Farnesylated Carboxy-Terminal Lamin Peptides

Epigentics of Aging, Department of Dermatology, TUM School of Medicine, Technical University of Munich, 85748 Garching-Munich, Germany
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Received: 28 February 2018 / Revised: 11 April 2018 / Accepted: 19 April 2018 / Published: 23 April 2018
(This article belongs to the Collection Lamins and Laminopathies)
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Abstract

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. View Full-Text
Keywords: progerin; nuclear envelope; autophagy; prelamin A; SUN1; farnesylation progerin; nuclear envelope; autophagy; prelamin A; SUN1; farnesylation
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Lu, X.; Djabali, K. Autophagic Removal of Farnesylated Carboxy-Terminal Lamin Peptides. Cells 2018, 7, 33.

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