Connecting the nucleus to the cytoskeleton by SUN-KASH bridges across the nuclear envelope

Abstract

The nuclear-cytoskeleton connection influences many aspects of cellular architecture, including nuclear positioning, the stiffness of the global cytoskeleton, and mechanotransduction. Central to all of these processes is the assembly and function of conserved SUN-KASH bridges, or LINC complexes, that span the nuclear envelope. Recent studies provide details of the higher order assembly and targeting of SUN proteins to the inner nuclear membrane. Structural studies characterize SUN-KASH interactions that form the central link of the nuclear-envelope bridge. KASH proteins at the outer nuclear membrane link the nuclear envelope to the cytoskeleton where forces are generated to move nuclei. Significantly, SUN proteins were recently shown to contribute to the progression of laminopathies.

Figure 1

SUN and KASH proteins span the nuclear envelope. A trimer of SUN proteins (light blue, dark blue, and grey) forms at the inner nuclear membrane (INM). SUN proteins interact with the KASH domain (orange) in the perinuclear space. Only a single KASH protein is shown for simplicity. KASH proteins cross the outer nuclear membrane (ONM) and extend into the cytoplasm to interact with the cytoskeleton. One class of KASH proteins (yellow) recruit microtubule motors dynein and kinesin to the surface of the nucleus, while a second class (light green) tethers nuclei to actin filaments.

Figure 2

Three steps to targeting SUN proteins to the inner nuclear membrane (INM). First, signals including INM-SM and SUN-NELS recruit partners to move SUN proteins from the peripheral ER to the outer nucear membrane (ONM). ATP and the Golgi retrieval signal (4R) also participate in this first step. Second, importins (red), ATP, and/or histone H2A.Z (pink) help shuttle SUN proteins across the nuclear pore. Finally, SUN proteins are retained at the INM by interacting with lamins and forming bridges with KASH proteins.

Figure 3

The crystal structure of the interaction between the SUN and KASH domains of human Sun2 and Nesprin-2. A surface representation of the three SUN protomers (shades of blue) and the backbone of the KASH peptide (orange) are shown from two angles. Adapted, with permission, from [16].