Work

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

Year: 2014

Type: article

Abstract: 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 (PGΔNLS and LAΔNLS, respectively) have been constructed. We find that both ΔNLS mutants are farnesylated in the cytosol and associate with a sub-domain of the ER via their farnesyl tails. While the farnesylation on LAΔNLS can be gradually removed, which leads to its subsequent release from the ER into the cytoplasm, PGΔNLS remains permanently farnesylated and membrane-bounded. Moreover, both ΔNLS mutants dominantly affect emerin's nuclear localization. These results reveal new insights into lamin A biogenesis and lamin A-emerin interaction.

Source: Nucleus

DOI: 10.4161/nucl.28068

Authors: Di Wu, Andrew R Flannery, Helen Cai, Eunae Ko, Kan Cao

Institution: University of Maryland, College Park

Language: English

Topic: Nuclear Structure and Function

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: gold

Estimated APC paid: $1,993

Funders: Ellison Medical Foundation, University of Maryland, National Institute on Aging