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.
Pubmed ID: 29690642 RIS Download
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View all literature mentionsThe mission of The Progeria Research Foundation is to discover treatments and the cure for Progeria, and its aging related disorders. Progeria is a rare and fatal genetic disease characterized by an appearance of accelerated aging in children. Without the discovery of new treatments, all children with Progeria will die of heart disease at an average age of 13 years. The Progeria Research Foundation (PRF) was founded in 1999 in response to the complete lack of progress being made to help children with Progeria. We have filled a void, taking these children out of the background where they had been for over 100 years and putting them and Progeria at the forefront of scientific efforts. In just 11.5 years, we have achieved extraordinary progress towards our mission: the Progeria gene discovery in 2003, first-ever clinical drug trials initiated in 2007, extensive global awareness of the disease and PRF''s work, and discovery of critical biological links between Progeria, heart disease and aging we all experience.
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View all literature mentionsCell line HeLa is a Cancer cell line with a species of origin Homo sapiens
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