Nuclear localization signal deletion mutants of lamin A and progerin reveal insights into lamin A processing and emerin targeting

作者：Wu Di; Flannery Andrew R; Cai Helen; Ko Eunae; Cao Kan^*

来源：Nucleus, 2014, 5(1): 66-74.

DOI：10.4161/nucl.28068

• progeria
• emerin
• lamin
• nuclear localization signal
• ZMPSTE24
• farnesylation

Lamin A is a major component of the lamina, which creates a dynamic network underneath the nuclear envelope. Mutations in the lamin A gene (LMNA) cause severe genetic disorders, one of which is Hutchinson-Gilford progeria syndrome (HGPS), a disease triggered by a dominant mutant named progerin. Unlike the wild-type lamin A, whose farnesylated C-terminus is excised during post-translational processing, progerin retains its farnesyl tail and accumulates on the nuclear membrane, resulting in abnormal nuclear morphology during interphase. In addition, membrane-associated progerin forms visible cytoplasmic aggregates in mitosis. To examine the potential effects of cytoplasmic progerin, nuclear localization signal (NLS) deleted progerin and lamin A (PG Delta NLS and LA Delta NLS, respectively) have been constructed. We find that both Delta NLS mutants are farnesylated in the cytosol and associate with a sub-domain of the ER via their farnesyl tails. While the famesylation on LA Delta NLS can be gradually removed, which leads to its subsequent release from the ER into the cytoplasm, PG Delta NLS remains permanently farnesylated and membrane-bounded. Moreover, both Delta NLS mutants dominantly affect emerin's nuclear localization. These results reveal new insights into lamin A biogenesis and lamin A-emerin interaction.

• 出版日期2014-2