Structural protein 4.1R is integrally involved in nuclear envelope protein localization, centrosome–nucleus association and transcriptional signaling

Abstract

SummaryThe multifunctional structural protein 4.1R is required for assembly and maintenance of functional nuclei but its nuclear roles are unidentified. 4.1R localizes within nuclei, at the nuclear envelope, and in cytoplasm. Here we show that 4.1R, the nuclear envelope protein emerin and the intermediate filament protein lamin A/C co-immunoprecipitate, and that 4.1R-specific depletion in human cells by RNA interference produces nuclear dysmorphology and selective mislocalization of proteins from several nuclear subcompartments. Such 4.1R-deficiency causes emerin to partially redistribute into the cytoplasm, whereas lamin A/C is disorganized at nuclear rims and displaced from nucleoplasmic foci. The nuclear envelope protein MAN1, nuclear pore proteins Tpr and Nup62, and nucleoplasmic proteins NuMA and LAP2 also have aberrant distributions, but lamin B and LAP2 have normal localizations. 4.1R-deficient mouse embryonic fibroblasts show a similar phenotype. We determined the functional effects of 4.1R-deficiency that reflect disruption of the association of 4.1R with emerin and A-type lamin: increased nucleus-centrosome distances, increased -catenin signaling, and relocalization of -catenin from the plasma membrane to the nucleus. Furthermore, emerin-and lamin-A/C-null cells have decreased nuclear 4.1R. Our data provide evidence that 4.1R has important functional interactions with emerin and A-type lamin that impact upon nuclear architecture, centrosome-nuclear envelope association and the regulation of -catenin transcriptional co-activator activity that is dependent on -catenin nuclear export.

The nuclear envelope LEM-domain protein emerin

“…Emerin also associates (at least indirectly; direct binding not tested) with the multifunctional structural protein 4.1R in vivo, which directly binds actin and spectrin to form a ternary complex, 130 and is required for mitotic spindle function and nuclear assembly 131 , 132 . The nuclear localizations of emerin and 4.1R are mutually dependent: loss of 4.1R decreases emerin retention at the INM and vice-versa, and loss of either protein increases accumulation of β-catenin in the nucleus 93 , 133 . The nucleoskeletal roles of actin, myosin, spectrin and 4.1 are major understudied areas of cell biology 2 …”

Lamins at a glance

“…In mammalian somatic cells, intranuclear (A-type) lamin structures and modulation of chromatin organization by lamins (see below) could further affect nuclear stiffness. A-type lamins also bind to numerous structural proteins, including B-type lamins, emerin, NUP153, lamina-associated polypeptide 2 isoform alpha (LAP2a), nesprins, SUNdomain-containing proteins, nuclear actin and protein 4.1R (see Poster) (Al-Haboubi et al, 2011;Lattanzi et al, 2003;Markiewicz et al, 2002a;Meyer et al, 2011;Sakaki et al, 2001;Sasseville and Langelier, 1998;Simon and Wilson, 2010). Intriguingly, A-type lamins, together with emerin, 4.1R, spectrin and actin, might form a structural network at the nuclear envelope (Meyer et al, 2011), further enhancing nuclear stability.…”

SUT Sucrose and MST Monosaccharide Transporter Inventory of the Selaginella Genome

“…The Drosophila homolog SCRT transports sucrose, is potentially located in intracellular melanosomes, and mutation leads to increased lethality. SRCT has been implicated in an essential role in transporting sucrose as an osmolytes as or as a nutrient (Meyer et al, 2011). Mutations in the mammalian SLC45 homologs lead to oculocutaneous albinism suggesting a critical role in melanosomes (Newton et al, 2001).…”