Dysregulated interactions between lamin A and SUN1 induce abnormalities in the nuclear envelope and endoplasmic reticulum in progeric laminopathies

• Published in: Journal of cell science Vol. 127; no. Pt 8; pp. 1792 - 1804
• Main Authors: Chen, Zi-Jie, Wang, Wan-Ping, Chen, Yu-Ching, Wang, Jing-Ya, Lin, Wen-Hsin, Tai, Lin-Ai, Liou, Gan-Guang, Yang, Chung-Shi, Chi, Ya-Hui
• Format: Journal Article
• Language: English
• Published: England 15.04.2014
• Subjects: Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - pathology; Fibroblasts - metabolism; HeLa Cells; Humans; Lamin Type A - genetics; Lamin Type A - metabolism; Membrane Proteins - metabolism; Microtubule-Associated Proteins - metabolism; Mitosis; Nuclear Envelope - metabolism; Nuclear Envelope - pathology; Nuclear Proteins - metabolism; Point Mutation; Prenylation; Progeria - genetics; Progeria - pathology; Protein Precursors - metabolism; Protein Processing, Post-Translational; Protein Transport; Skin - pathology; SUN1; HGPS; Nuclear envelope; Progeria; Lamin A
• ISSN: 0021-9533; 1477-9137
• DOI: 10.1242/jcs.139683

Hutchinson-Gilford progeria syndrome (HGPS) is a human progeroid disease caused by a point mutation on the LMNA gene. We reported previously that the accumulation of the nuclear envelope protein SUN1 contributes to HGPS nuclear aberrancies. However, the mechanism by which interactions between mutant lamin A (also known as progerin or LAΔ50) and SUN1 produce HGPS cellular phenotypes requires further elucidation. Using light and electron microscopy, this study demonstrated that SUN1 contributes to progerin-elicited structural changes in the nuclear envelope and the endoplasmic reticulum (ER) network. We further identified two domains through which full-length lamin A associates with SUN1, and determined that the farnesylated cysteine within the CaaX motif of lamin A has a stronger affinity for SUN1 than does the lamin A region containing amino acids 607 to 656. Farnesylation of progerin enhanced its interaction with SUN1 and reduced SUN1 mobility, thereby promoting the aberrant recruitment of progerin to the ER membrane during postmitotic assembly of the nuclear envelope, resulting in the accumulation of SUN1 over consecutive cellular divisions. These results indicate that the dysregulated interaction of SUN1 and progerin in the ER during nuclear envelope reformation determines the progression of HGPS.