From loss to gain: role for SUN1 in laminopathies

The nuclear envelope (NE) is a double-layered membrane separating the cell’s genetic material from the cytoplasm. The outer nuclear membrane (ONM) fuses with the inner nuclear membrane (INM) around the nuclear pore complex and extends to the endoplasmic reticulum (ER). Right underneath the INM is a layer of fine meshwork, namely nuclear lamina wherein various lamins and interacting proteins reside. A group of SUN (Sad1/UNC-84 homology) domain-containing proteins anchor to the INM and interact with different lamins, on the lamina, and nesprins, on the ONM, thus bridging nucleoskeleton and cytoskeleton. As one of the major components of the nuclear lamina (Figure？1), lamin A is firstly synthesized as prelamin A with an extra 18 amino acids at the C-terminus, which undergo transient isoprenylation, methylation, and these residues are finally removed by proteolytic cleavage [1]. To date, more than 237 LMNA mutations, leading to at least 163 protein variants, are known to be associated with at least 10 different degenerative disorders, collectively referred to as laminopathy. Some of these degenerative features are recapitulated in mice deficient for Lmna or harboring various Lmna mutations. Homozygous LmnaL530P/L530P mutation (Lmna？9 or Lamin A？Exon9) or loss of prelamin A-processing metalloproteinase Zmpste24 in mice phenocopies many of the progeroid features observed in Hutchinson-Gilford progeria syndrome (HGPS), one of the most severe forms of laminopathy that are predominantly caused by a 50-amino-acid deletion in prelamin A (lamin A？50 or progerin). Currently, the phenotypes in various mouse models and human diseases are thought to be attributable to either loss or gain of function of lamin A mutants.A recent paper further highlights the gain-of-function versus loss-of-function model for the action of lamin A in laminopathies [2]. Chen et al. found that the level of Sun1 protein was up-regulated and mislocalized to Golgi in Lmna？/？ and Lmna？9 cells. Although Golgi