Hutchinson-Gilford progeria syndrome (HGPS) is a human progeroid disease caused by a point mutation on the LMNA gene. We have previously reported that the accumulation of the nuclear envelope (NE) protein, SUN1, contributes to HGPS nuclear aberrancies. However, how the interaction between the mutant lamin A (also known as progerin or LAΔ50) and SUN1 produces 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. This study identified the full-length lamin A associated with SUN1 in two domains, with the farnesylated cysteine within the CaaX motif (C661farnesyl) showing a stronger affinity to SUN1 than to the amino acids within 607 to 656 (LMNA-SID). 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, and 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:
FASEB Journal. 2014 Apr;28(1 Suppl.):Article number 1009.1.
