Integral membrane proteins of the inner nuclear membrane (INM) are inserted into the
endoplasmic reticulum membrane during their biogenesis and are then targeted to their
final destination. We have used human SUN2 to delineate features that are required
for INM targeting and have identified multiple elements that collectively contribute
to the efficient localization of SUN2 to the nuclear envelope (NE). One such targeting
element is a classical nuclear localization signal (cNLS) present in the N-terminal,
nucleoplasmic domain of SUN2. A second motif proximal to the cNLS is a cluster of
arginines that serves coatomer-mediated retrieval of SUN2 from the Golgi. Unexpectedly,
also the C-terminal, lumenal SUN domain of SUN2 supports NE localization, showing
that targeting elements are not limited to cytoplasmic or transmembrane domains of
INM proteins. Together, SUN2 represents the first mammalian INM protein relying on
a functional cNLS, a Golgi retrieval signal and a perinuclear domain to mediate targeting
to the INM. The EMBO Journal (2010) 29, 2262-2275. doi:10.1038/emboj.2010.119; Published
online 15 June 2010
