Many mechanisms, one entrance: membrane protein translocation into the nucleus

Zuleger, Nikolaj; Kerr, Alastair; Schirmer, Eric C.

doi:10.1007/s00018-012-0929-1

Cited by 47 publications

(52 citation statements)

References 93 publications

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“…In agreement with the established membrane topology of fulllength GlyRs (Breitinger and Becker, 2002;Zuleger et al, 2012), the large cytosolic loop domain between transmembrane segments 3 and 4 of intranuclear GlyRs will be exposed to genomic DNA in the nucleoplasm of glioma cells. In fact, Cys-loop neurotransmitter receptors have a common origin (Tasneem et al, 2004), and our BLAST search of the NCBI prokaryote database revealed substantial (,30%) similarity between the large cytosolic GlyR loop domain encoded by exon 9 and prokaryotic proteins with molecular chaperone function (proteasome-activating nucleotidase, sequence ID: gb|ADD93104.1) or DNA-processing activity (type III restriction protein res subunit, sequence ID: gb|EMA60229.1).…”

Section: Discussionsupporting

confidence: 65%

Intracellular glycine receptor function facilitates glioma formation in vivo

Förstera

Dzaye

Winkelmann

et al. 2014

Journal of Cell Science

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BSTRACTThe neuronal function of Cys-loop neurotransmitter receptors is established; however, their role in non-neuronal cells is poorly defined. As brain tumors are enriched in the neurotransmitter glycine, we studied the expression and function of glycine receptors (GlyRs) in glioma cells. Human brain tumor biopsies selectively expressed the GlyR a1 and a3 subunits, which have nuclear localization signals (NLSs). The mouse glioma cell line GL261 expressed GlyR a1, and knockdown of GlyR a1 protein expression impaired the self-renewal capacity and tumorigenicity of GL261 glioma cells, as shown by a neurosphere assay and GL261 cell inoculation in vivo, respectively. We furthermore showed that the pronounced tumorigenic effect of GlyR a1 relies on a new intracellular signaling function that depends on the NLS region in the large cytosolic loop and impacts on GL261 glioma cell gene regulation. Stable expression of GlyR a1 and a3 loops rescued the self-renewal capacity of GlyR a1 knockdown cells, which demonstrates their functional equivalence. The new intracellular signaling function identified here goes beyond the well-established role of GlyRs as neuronal ligand-gated ion channels and defines NLS-containing GlyRs as new potential targets for brain tumor therapies.

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Section: Discussionsupporting

confidence: 65%

Intracellular glycine receptor function facilitates glioma formation in vivo

Förstera

Dzaye

Winkelmann

et al. 2014

Journal of Cell Science

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“…Compared to nuclear import of soluble proteins, targeting of proteins to the INM is not well characterized (Burns and Wente, 2012;Zuleger et al, 2012). Soullam and Worman (1995) identified specific INM-targeting signals within a nuclear region of the lamin B receptor (LBR), which comprises eight predicted transmembrane domains.…”

Section: Introductionmentioning

confidence: 99%

Emery–Dreifuss muscular dystrophy mutations impair TRC40-mediated targeting of emerin to the inner nuclear membrane

Pfaff

Rivera‐Monroy

Jamieson

et al. 2016

Journal of Cell Science

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Emerin is a tail-anchored protein that is found predominantly at the inner nuclear membrane (INM), where it associates with components of the nuclear lamina. Mutations in the emerin gene cause EmeryDreifuss muscular dystrophy (EDMD), an X-linked recessive disease. Here, we report that the TRC40/GET pathway for post-translational insertion of tail-anchored proteins into membranes is involved in emerin-trafficking. Using proximity ligation assays, we show that emerin interacts with TRC40 in situ. Emerin expressed in bacteria or in a cell-free lysate was inserted into microsomal membranes in an ATP-and TRC40-dependent manner. Dominant-negative fragments of the TRC40-receptor proteins WRB and CAML (also known as CAMLG) inhibited membrane insertion. A rapamycin-based dimerization assay revealed correct transport of wild-type emerin to the INM, whereas TRC40-binding, membrane integration and INMtargeting of emerin mutant proteins that occur in EDMD was disturbed. Our results suggest that the mode of membrane integration contributes to correct targeting of emerin to the INM.

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“…For instance, it is still unclear how INM proteins exactly pass the NPC en route to their destination, after membrane insertion in the ER via the Sec61 channel. If these INM proteins, in fact, stay membrane inserted during NPC passage, it is most likely that they pass through peripheral pore channels between outer coat and pore membrane (Zuleger et al 2012). Cryo-ET studies of the NPC clearly indicate the existence of peripheral channels 8 nm wide (Beck et al 2007;Maimon et al 2012).…”

Section: T Schwartzmentioning

confidence: 99%

Functional Insights from Studies on the Structure of the Nuclear Pore and Coat Protein Complexes

Schwartz

2013

Cold Spring Harbor Perspectives in Biology

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The nuclear envelope (NE) is a specific extension of the endoplasmic reticulum (ER) that wraps around the nucleus and enables the spatial separation of gene transcription and protein translation, one of the signature features of eukaryotes. Rather than being completely closed, the double lipid bilayer of the NE is perforated at sites where the inner and outer nuclear membranes fuse, resulting in circular openings lined with sharply bent membranes. These openings are filled with nuclear pore complexes (NPCs), enormous protein assemblies that facilitate nuclear transport. The scaffold components of the NPC surprisingly share interesting similarities with elements of coat protein complexes, which have general implications for function and evolution of these membrane-coating complexes. Here I discuss, from a structural perspective, what these findings might teach us.A s discussed in other articles, the endoplasmic reticulum (ER) is a structurally and functionally diverse organelle. The nuclear envelope (NE) is perhaps the most extreme substructure of the ER. It consists of two flat nuclear membrane sheets that are kept apart in a well-defined distance of 5 nm and that encapsulate the genetic material of the eukaryotic cell (Stewart et al. 2007;Mekhail and Moazed 2010 Grossman et al. 2012). In electron micrographs, NPCs appear as hollow cylinders with distinct cytoplasmic and nucleoplasmic faces, and have an overall eightfold rotational symmetry (Goldberg and Allen 1996). The best-resolved NPC images are obtained by cryoelectron tomography (cryo-ET), reaching a resolution of up to 6 nm ( Fig. 1) (Beck et al. 2004(Beck et al. , 2007Maimon et al. 2012). In cryo-ET, various building blocks of the NPC can be distinguished, yet individual proteins are not resolved. On the cytoplasmic side of the pore, fiber-like extensions emanate from the central NPC mass.On the nucleoplasmic side, eight filaments protrude and cojoin in a narrow ring, a component named a "fishtrap" or "basket." The central Figure 1. The nuclear pore complex. (A) Cryo-electron tomographic reconstruction of the NPC from Dictyostelium discoideum at 6-nm resolution. Cutaway view across the nuclear envelope (NE). The NPC appears organized into three stacked rings that cover the circular openings in the NE. NPCs show eightfold rotational ring symmetry. On the nucleoplasmic side, eight filaments protrude and cojoin in a ring. This resolution reveals the overall dimensions of the NPC and its most prominent features (labeled). (B) Nucleoporins are organized into subcomplexes that are well conserved across divergent eukaryotes. The main NPC scaffold is likely made up of two heteromeric subassemblies, the Y-complex (dark blue) and the Nic96 or Nup93 complex (light blue). The components of these subassemblies have architectural domains, mainly composed of a-helical stack domains and b-propellers. These scaffold complexes are connected to the pore membrane via membrane proteins (yellow). The other subassemblies of the NPC decorate the main scaffold and perform the m...

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Many mechanisms, one entrance: membrane protein translocation into the nucleus

Cited by 47 publications

References 93 publications

Intracellular glycine receptor function facilitates glioma formation in vivo

Intracellular glycine receptor function facilitates glioma formation in vivo

Emery–Dreifuss muscular dystrophy mutations impair TRC40-mediated targeting of emerin to the inner nuclear membrane

Functional Insights from Studies on the Structure of the Nuclear Pore and Coat Protein Complexes

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