Hutchinson-Gilford progeria syndrome (HGPS) is a human progeroid disease caused by a point mutation on the LMNA gene. We previously reported that the accumulation of the nuclear envelope (NE) protein SUN1 contributes to HGPS nuclear aberrancies. However, the mechanism by which interactions between mutant lamin A (also known as progerin or LADelta50) 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 NE and the endoplasmic reticulum (ER) network. We further identified two domains where full-length lamin A associates with SUN1, and determined that the farnesylated cysteine within the CaaX motif has a stronger affinity to SUN1 than to the amino acids within 607 to 656. Farnesylation of progerin enhances its interaction with SUN1 and reduces SUN1 mobility, thereby promoting the aberrant recruitment of 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 NE reformation determines the progression of HGPS.
Date:
2014-04
Relation:
Journal of Cell Science. 2014 Apr;127(8):1792-1804.
