SUN1 splice variants, SUN1_888, SUN1_785, and predominant SUN1_916, variably function in directional cell migration

The LINC complex is a multifunctional protein complex that is involved in various processes at the nuclear envelope, such as nuclear migration, mechanotransduction and chromatin tethering in the meiotic phase. However, it remains unknown how these functions are regulated in different cell contexts. An inner nuclear membrane component of the LINC complex, SUN1, is ubiquitously expressed. The human SUN1 gene produces over 10 variants by alternative splicing. Although functions of SUN1 are relatively well characterized, functional differences among SUN1 splice variants are poorly characterized. LINC complex components are associated with a wide range of human diseases; therefore, it is important to understand the functional diversity among SUN1 splice variants. Here, we identified a novel human SUN1 splice variant, SUN1_888. overexpression of the SUN1 splice variants, SUN1_888 or SUN1_785, but not the predominant isoform, SUN1_916, activated directional cell migration. Knockdown of SUN1_888 suppressed cell migration; in contrast depletion of SUN1_916 activated cell migration. In addition, all of investigated SUN1 splicing variants rescued cell migration in SUN1 knock out cell. These results indicate that redundant and non-redundant functions of SUN1 splice variant in directional cell migration and suggest that variable LINC complexes with distinct task may exit. Furthermore, in contrast to previous studies, we showed association between SUN1 and B-type lamins. Interestingly, B-type lamin preferentially interacts with SUN1 but not SUN2. These results suggest that tissue-specific SUN1 variants variably interact with nucleoplasmic partners and allow variable assembly of LINC complexes that can be assigned to distinct tasks.