Protein translocation: Nuclear export –  out of the dark

Moore, Mary Shannon

doi:10.1016/s0960-9822(02)00444-x

Cited by 20 publications

(13 citation statements)

References 20 publications

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“…Not only do yeast and human Ntf2p interact with themselves, they also interact with each other. Also, in agreement with biochemical data, human Ran can interact with human Ntf2p (Table 1) (17,49,55,59). It is also interesting to note that both Gsp1p and Ran can interact with either yeast or human Ntf2p, indicating that their interaction is conserved between species (Table 1).…”

Section: Resultssupporting

confidence: 83%

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Interaction between the Small GTPase Ran/Gsp1p and Ntf2p Is Required for Nuclear Transport

Wong

Corbett

Kent

et al. 1997

Molecular and Cellular Biology

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Bidirectional movement of proteins and RNAs across the nuclear envelope requires Ran, a Ras-like GTPase. A genetic screen of the yeast Saccharomyces cerevisiae was performed to isolate conditional alleles of GSP1, a gene that encodes a homolog of Ran. Two temperature-sensitive alleles, gsp1-1 and gsp1-2, were isolated. The mutations in these two alleles map to regions that are structurally conserved between different members of the Ras family. Each mutant strain exhibits various nuclear transport defects. Both biochemical and genetic experiments indicate a decreased interaction between Ntf2p, a factor which is required for protein import, and the mutant GSP1 gene products. Overexpression of NTF2 can suppress the temperature sensitive phenotype of gsp1-1 and gsp1-2 and partially rescue nuclear transport defects. However, overexpression of a mutant allele of NTF2 with decreased binding to Gsp1p cannot rescue the temperature sensitivity of gsp1-1 and gsp1-2. Taken together, these data demonstrate that the interaction between Gsp1p and Ntf2p is critical for nuclear transport.

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Section: Resultssupporting

confidence: 83%

“…To validate this approach, we tested whether or not two-hybrid constructs for NTF2 and GSP1 interact as they do in biochemical assays. Various studies have shown that Ntf2p forms a dimer (14,49,59). In a two-hybrid assay, Ntf2p interacts with itself indicating that Ntf2p also dimerizes in yeast (Table 1).…”

Section: Resultsmentioning

confidence: 98%

Interaction between the Small GTPase Ran/Gsp1p and Ntf2p Is Required for Nuclear Transport

Wong

Corbett

Kent

et al. 1997

Molecular and Cellular Biology

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“…Moreover, several studies highlight the involvement of members of the protein disulfide isomerase (PDI) family in the preparation of misfolded polypeptides for dislocation across the ER membrane and in transport across the bilayer of virions and of catalytic subunits of toxins. For example, intra‐ and intermolecular disulfide bonds in ERAD substrates as well as interchain disulfides linking the regulatory and catalytic subunits of bacterial toxins are reduced with the intervention of PDI and/or PDI family members (e.g. ERdj5 , ERp57 , ERp72, ERp29 , TMX1 , ERFAD‐ERp90 and ERO1 ).…”

Section: Specificity Of the Erad Machinerymentioning

confidence: 99%

Specificity and Regulation of the Endoplasmic Reticulum‐Associated Degradation Machinery

Merulla

Fasana

Soldà

et al. 2013

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The endoplasmic reticulum-associated degradation (ERAD) machinery selects native and misfolded polypeptides for dislocation across the ER membrane and proteasomal degradation. Regulated degradation of native proteins is an important aspect of cell physiology. For example, it contributes to the control of lipid biosynthesis, calcium homeostasis and ERAD capacity by setting the turnover rate of crucial regulators of these pathways. In contrast, degradation of native proteins has pathologic relevance when caused by viral or bacterial infections, or when it occurs as a consequence of dysregulated ERAD activity. The efficient disposal of misfolded proteins prevents toxic depositions and persistent sequestration of molecular chaperones that could induce cellular stress and perturb maintenance of cellular proteostasis. In the first section of this review, we survey the available literature on mechanisms of selection of native and non-native proteins for degradation from the ER and on how pathogens hijack them. In the second section, we highlight the mechanisms of ERAD activity adaptation to changes in the ER environment with a particular emphasis on the post-translational regulatory mechanisms collectively defined as ERAD tuning. The cellular proteome is mostly synthesized by cytosolic ribosomes to operate in the cytosol and, upon appropriate targeting, in various intracellular organelles or in the extracellular space. Cellular compartments where protein folding occurs [e.g. the cytosol, mitochondria, the endoplasmic reticulum (ER)] contain two classes of non-native polypeptides: (i) newly synthesized polypeptide chains that must be assisted by folding chaperones and enzymes to attain the native mono-or oligomeric structure; (ii) terminally misfolded conformers that must efficiently be degraded to prevent the formation of toxic deposits and the persistent sequestration of chaperones that could eventually inhibit the cellular protein folding capacity and elicit stress (1-3) ( Figure 1A). The distinction between the two classes of non-native chains, one to be preserved, the second to be cleared from the folding compartment, is not an easy task for the cellular quality control machineries. Selection for disposal might be a stochastic process: the longer the persistency of structural defects in the ER, the greater is the probability to be selected for destruction. Therefore, mutations that delay folding may channel the polypeptide into destructive pathways, even if they do not compromise the function of the mutated protein.In the ER, non-native, but also native proteins might be selected for degradation by components of the endoplasmic reticulum-associated degradation (ERAD) machinery that deliver them at dislocation sites embedded in the ER membrane. Dislocation sites consist of a multitude of luminal and membrane-bound specialized ER-resident proteins as well as a number of cytosolic factors insuring dislocation across the ER membrane, poly-ubiquitylation and disposal of ERAD substrates by 26S proteasomes (Specificity of...

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“…Specific nuclear export signals (NES) have been identified in several shuttling proteins, such as hnRNP A1, a heat-stable inhibitor peptide (PKI) of protein kinase A, and the viral protein HIV-1 Rev (for review, see Moore 1996). In the case of hnRNP A1, the M9 sequence is responsible for both nuclear localization and for nuclear export (Michael et al 1995b;Siomi and Dreyfuss 1995;Weighardt et al 1995).…”

Section: Shuttling Mechanismsmentioning

confidence: 99%

A specific subset of SR proteins shuttles continuously between the nucleus and the cytoplasm

Cáceres¹,

Screaton²,

Krainer³

1998

Genes Dev.

437

353

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The SR proteins constitute a large family of nuclear phosphoproteins required for constitutive pre-mRNA splicing. These factors also have global, concentration-dependent effects on alternative splicing regulation and this activity is antagonized by members of the hnRNP A/B family of proteins. We show here that whereas some human SR proteins are confined to the nucleus, three of them-SF2/ASF, SRp20, and 9G8-shuttle rapidly and continuously between the nucleus and the cytoplasm. By swapping the corresponding domains between shuttling and nonshuttling SR proteins, we show that the carboxy-terminal arginine/serine-rich (RS) domain is required for shuttling. This domain, however, is not sufficient to promote shuttling of an unrelated protein reporter, suggesting that stable RNA binding mediated by the RNA-recognition motifs may be required for shuttling. Consistent with such a requirement, a double point-mutation in RRM1 of SF2/ASF that impairs RNA binding prevents the protein from shuttling. In addition, we show that phosphorylation of the RS domain affects the shuttling properties of SR proteins. These findings show that different SR proteins have unique intracellular transport properties and suggest that the family members that shuttle may have roles not only in nuclear pre-mRNA splicing but also in mRNA transport, cytoplasmic events, and/or processes that involve communication between the nucleus and the cytoplasm. The SR proteins are closely related, highly conserved RNA-binding proteins that have dual roles in pre-mRNA splicing. They are essential for constitutive splicing and also regulate splicing in a concentration-dependent manner by influencing the selection of alternative splice sites (Ge and Manley 1990; Krainer et al. 1990a,b;Zahler et al. 1993; for review, see Fu 1995; Manley and Tacke 1996; Cá ceres and Krainer 1997). The activity of SR proteins in regulated splicing is antagonized by members of the hnRNP A/B family of proteins (Mayeda and Krainer 1992;Mayeda et al. 1994) and alterations in the ratio of these antagonistic factors cause drastic changes in splice-site selection both in vitro and in vivo (Mayeda and Krainer 1992;Cá ceres et al. 1994;Yang et al. 1994). The relative abundance of each SR protein and the molar ratio of each SR protein to hnRNP A1 or to other antagonists may therefore determine the patterns of alternative splicing of many genes expressed in specific cell types. Tissue-specific variations in the total and relative amounts of SR proteins or mRNAs have been described (for review, see Cá ceres and Krainer 1997) and in addition, the molar ratio of SF2/ASF to hnRNPA1 varies over a wide range in different rat tissues (A. Hanamura, J.F. Cá ceres, A. Mayeda, and A.R. Krainer, in prep.).The SR proteins are nuclear phosphoproteins that are concentrated, together with most other splicing factors, in nuclear subregions termed speckles. The speckle domain seen by immunofluorescence corresponds to interchromatin granule clusters and perichromatin fibrils at the electron microscope level (f...

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Protein translocation: Nuclear export – out of the dark

Abstract: Nuclear protein export has, in contrast to nuclear protein import, been a poorly understood process; but now, the signals and cellular machinery that govern protein export from the nucleus are beginning to be elucidated.

Cited by 20 publications

References 20 publications

Interaction between the Small GTPase Ran/Gsp1p and Ntf2p Is Required for Nuclear Transport

Interaction between the Small GTPase Ran/Gsp1p and Ntf2p Is Required for Nuclear Transport

Specificity and Regulation of the Endoplasmic Reticulum‐Associated Degradation Machinery

A specific subset of SR proteins shuttles continuously between the nucleus and the cytoplasm

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