Ran in Mitosis - Ras Superfamily Small G Proteins: Biology and Mechanisms 2 - page 138

7.8 Ran and Importins in Primary Cilia Formation

The molecular analysis of nucleocytoplasmic transport started with the character-
ization of nuclear protein import as an active, i.e. energy-dependent, saturable and
signal (i.e. NLS)-mediated process (Goldfarb et al. 1986 ). Later, it turned out that
nuclear protein import requires soluble transport receptors (Adam et al. 1990 ),
which directly recognise the NLS (G¨rlich et al. 1994 ; Weis et al. 1995 ). A similar
concept was recently suggested to work for the selective import of proteins, which
are destined for primary cilia. The vast majority of human cells assemble primary
cilia to function as cellular “antennae” in sensing environmental cues and to convert
respective stimuli to the cytoplasm and the nucleus. The structure of primary cilia
reflects their specific function. Cilia are generated around the unique microtubule
array of the axoneme, which initially assembles and elongates from the centriole-
based basal body. The ciliary (axonemal) MTs are surrounded by a specialised
ciliary membrane. Both the membrane and the interior of the cilium comprise a
unique set of proteins, which are targeted there by selective, signal-mediated
transport processes. Consistently, primary cilia seal themselves from the cytoplasm
by transitional elements that assemble from the basal body to reach the plasma
membrane and to limit diffusion of large molecules into cilia. Signals recognised as
“ciliary targeting signals (CLS)” often contain short stretches of basic amino acids
and are in some cases remarkably similar to NLSs. They can even function in
nuclear targeting if other important ciliary determinants in the primary structure are
deleted (Dishinger et al. 2010 ). Indeed, targeting of ciliary motor protein Kif17
turned out to rely on importin

2/transportin and, apparently, RanGTP, which
seems to accumulate inside the primary cilium (Dishinger et al. 2010 ). These
observations open up the intriguing possibility that nuclear import and ciliary
targeting may share similar principles and use an overlapping set of proteins for
targeting (Gruss 2010 ). Consistent with that, the permeability barrier made up of
transitional elements at the base of primary cilia was suggested to contain NPC
proteins (Kee et al. 2012 ). However, experimental evidence is lacking for several
key features of the model, such as proof for an active nucleotide exchange factor for
Ran, which constantly produces RanGTP to maintain the necessary high RanGTP
concentration inside the ciliary compartment. Moreover, although some NPCs were
found accumulating at transitional elements, there is no indication for any regular
structure similar to NPCs at the ciliary transition zone. It will thus be a very
interesting topic in the future to understand parallels and specific differences
between nuclear import and ciliary protein targeting and transport.

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References

Adam SA, Marr RS, Gerace L (1990) Nuclear protein import in permeabilized mammalian cells
requires soluble cytoplasmic factors. J Cell Biol 111:807-816
Arnaoutov A, Azuma Y, Ribbeck K, Joseph J, Boyarchuk Y, Karpova T, McNally J, Dasso M
(2005) Crm1 is a mitotic effector of Ran-GTP in somatic cells. Nat Cell Biol 7:626-632