Lamina Proteins in the Nuclear Interior

Lamins were traditionally regarded as proteins of the nuclear periphery, but with the availability of novel tools and microscopic techniques the concept of intranuclear lamins has recently developed. Since the nuclear membrane forms extensive tubular invaginations projecting deep into the nuclear interior,53 it is often hard to distinguish whether observed internal lamin structures are still associated with the invaginated nuclear membrane or whether they are truly intranuclear, apart from the nuclear membrane. Nevertheless, specific antibodies,34,54 several microscopical preparations techniques,55,56 and the use of expressed green fluorescent protein- (GFP) fusions of lamins,57,58 have revealed intranuclear lamin structures in foci or along filamentous structures or diffusely distributed throughout the nuclear interior. Although B-type lamins may also localize to intranuclear replication sites59 and a minor fraction of GFP-lamin B has been detected in stable intranuclear structures by fluorescence recovery after photobleaching (FRAP) analysis,58 the majority of studies have revealed particularly A-type lamins in the nuclear interior. This observation is consistent with the lack of C-terminal farnesyl modification of mature A-type lamins and the less stable association with the peripheral nuclear membrane and the nuclear lamina as compared with B-type lamins (see above).

Intranuclear A-type lamins may exist in a complex with LAP2a, the only LAP2 isoform not integrated into the membrane. LAP2a is a nucleoskeletal protein, based on its resistance to extraction by detergents and high salt,33 and was found to directly interact with the C-terminal tail region of mature lamins A and C in vitro.34 Furthermore, selective disruption of endogenous lamin A structures upon ectopic expression of dominant-negative lamin mutants in Hela cells caused a relocalization of LAP2a to intranuclear lamin A/C aggregates, but had no effect on lamin B, LAP2P, or NuMa.34 It is still unclear, however, whether lamin A and LAP2a form filaments or other higher order structures of the nuclear scaffold, or whether they exist as smaller complexes involved in the regulation of nuclear processes (see below). It is also not known, whether there is continuity between peripheral and internal nuclear lamin A structures or whether lamin subunits steadily exchange between these two subnuclear compartments.

Several laboratories have reported a transient localization of A-type lamins in the nuclear interior before their assembly into the nuclear lamina. FRAP analyses in GFP-lamin A expressing cells showed that the assembly of lamin A into peripheral nuclear structures is a late event in post-mitotic nuclear reformation,58 leading to accumulation of the majority of lamins A and C in the nuclear interior in G1 phase.34,60 Furthermore, microinjected lamin A and/or lamin C were found to first accumulate in nucleoplasmic foci, before the majority was incorporated into the nuclear lamina.61,62 As non-processed lamin A (missing the farnesyl modification) accumulated in similar intranuclear foci,63,64 transient intranuclear localization of lamin A might be directly linked to its post-translational processing, but the molecular mechanisms remain unclear. Recently, a novel nuclear protein of unknown cellular function, Narf, has been identified by yeast two-hybrid-screens as a direct and specific interaction partner of unprocessed lamin A.65

Farnesylation and C-terminal proteolytic cleavage ofA-type lamins during maturation can, however, not be the only reason for their transient accumulation in the nucleus, as intranuclear lamin A found in late stages of post-mitotic nuclear reformation is fully processed, and lamin C, which was also found to accumulate in intranuclear structures,62 is not processed at all. Thus, other modifications such as (de-) phosphorylation,66 or specific interactions with still unknown nuclear proteins might also be required for correct targeting of A-type lamins to peripheral as well as intranuclear structures.

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