The nucleus is separated from the cytoplasm by a selective structural barrier - the nuclear envelope in eukaryotic cells. The nuclear envelope is composed of inner and outer nuclear membranes (INM and ONM) separated by a perinuclear space (PNS). The specific INM integral proteins interact with the nuclear lamina and are associated with a variety of human diseases, collectively termed nuclear envelopathies. In eukaryotes the SUN domain proteins form a conserved family, the majority of which localize to the INM. UNC-84, which is the first SUN domain protein discovered in Caenorhabditis elegans, has been well studied and shown to be involved in nuclear anchorage and migration. Sun1, a novel INM protein, is the closest homolog to Caenorhabditis elegans UNC-84 in mammals. We show that Sun1 is broadly expressed in various mouse tissues. It spans the inner nuclear membrane three times via transmembrane domains with the N-terminus facing the nucleoplasm and the C-terminus residing in the perinuclear space. Like other inner nuclear membrane proteins Sun1 interacts with chromatin. Sun1 proteins are able to form homo-oligomers with a reduced lateral mobility, which are further stabilized by disulfide bonds. Sun1 can also oligomerize with Sun2, another SUN domain paralogous mammalian protein, at the nuclear envelope. The Sun1 C-terminus directly interacts with the KASH domain of Nesprins. These nuclear spectrin repeat containing proteins are able to bind directly to the actin cytoskeleton. Furthermore, we demonstrated that Sun1 is required for the proper nuclear envelope localization of Nesprin-1 and -2 by RNA interference and dominant negative interference studies. Together these data support a model in which SUN proteins tether Nesprins at the envelope via interactions inside the perinuclear space. In this way, SUN proteins and Nesprins form a physical link between the nucleoskeleton and cytoskeleton. We propose that SUN domain proteins by serving as mechanical adaptors and nuclear envelope receptors allow the physical integration and signaling interplay of cytoplasmic and nucleoplasmic compartments
