KASHing up with the nucleus: novel functional roles of KASH proteins at the cytoplasmic surface of the nucleus

Abstract

Nuclear-cytoskeletal connections are central to fundamental cellular processes, including nuclear positioning and chromosome movements in meiosis. The cytoskeleton is coupled to the nucleoskeleton through conserved KASH-SUN bridges, or LINC complexes, that span the nuclear envelope. KASH proteins localize to the outer nuclear membrane where they connect the nucleus to the cytoskeleton. New findings have expanded the functional diversity of KASH proteins, showing that they interact with microtubule motors, actin, intermediate filaments, a nonconventional myosin, RanGAP, and each other. The role of KASH proteins in cellular mechanics is discussed. Genetic mutations in KASH proteins are associated with autism, hearing loss, cancer, muscular dystrophy and other diseases.

Figure 1. Functions of KASH proteins at the cytoplasmic face of the nucleus

SUN proteins form trimers in the inner nuclear membrane with their conserved SUN domains (red) and coiled domains in the lumen of the nuclear envelope and nucleoplasmic domains (yellow). SUN domains interact with the KASH domain (light blue) in the lumen of the nuclear envelope. The cytoplasmic domains of KASH proteins (various shades of blue) are on the outer surface of the nucleus. SUN and KASH proteins are thought to interact in a three-to-three ratio. Only one or two KASH proteins are shown for each complex for simplicity. (A) Giant KASH proteins made of spectrin repeats tether the nucleus to actin networks. (A–B) Giant KASH proteins also interact with nesprin-3 to form a cage around the nucleus. (B) Nesprin-3 interacts with intermediate filaments through plectin. (C) KASH proteins recruit kinesin-1 to move nuclei. (D) KASH proteins recruit dynein to move nuclei, telomeres (or pairing centers in worms) or to connect centrosomes. (E) The plant KASH proteins WIP1, 2, and 3 interact with WITs (gren) to recruit a myosin-XI to move nuclei, and a RanGAP to catalyze the hydrolosis of GTP in Ran (pink) as it exits the nucleus. (F) The worm KASH protein KDP-1 regulates the cell cycle through unknown mechanisms. (G) Yeast Csm4 fits the definition of a KASH protein used to move telomeres along actin. (H) A novel kinesin-13 is a KASH protein that functions to attach the centrosome to nuclei. The names of KASH proteins from various systems, including humans (Hs), roundworms (Ce), fruit flies (Dm), zebrafish (Dr), fission yeast (Sp), budding yeast (Sc), slime molds (Dd), and angiosperms (At) are indicated.