scholarly journals Integral membrane proteins Brr6 and Apq12 link assembly of the nuclear pore complex to lipid homeostasis in the endoplasmic reticulum

2009 ◽  
Vol 123 (1) ◽  
pp. 141-151 ◽  
Author(s):  
C. A. Hodge ◽  
V. Choudhary ◽  
M. J. Wolyniak ◽  
J. J. Scarcelli ◽  
R. Schneiter ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Membrane Proteins ◽  
Nuclear Pore Complex ◽  
Integral Membrane Proteins ◽  
Lipid Homeostasis ◽  
Nuclear Pore

scholarly journals Brr6 and Brl1 locate to nuclear pore complex assembly sites to promote their biogenesis

2018 ◽  
Vol 217 (3) ◽  
pp. 877-894 ◽  
Author(s):  
Wanlu Zhang ◽  
Annett Neuner ◽  
Diana Rüthnick ◽  
Timo Sachsenheimer ◽  
Christian Lüchtenborg ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Nuclear Envelope ◽  
Nuclear Pore Complex ◽  
Lipid Composition ◽  
Fluorescent Protein ◽  
Yellow Fluorescent Protein ◽  
Protein Analysis ◽  
Integral Membrane Proteins ◽  
Nuclear Pore ◽  
Direct Role

The paralogous Brr6 and Brl1 are conserved integral membrane proteins of the nuclear envelope (NE) with an unclear role in nuclear pore complex (NPC) biogenesis. Here, we analyzed double-degron mutants of Brr6/Brl1 to understand this function. Depletion of Brr6 and Brl1 caused defects in NPC biogenesis, whereas the already assembled NPCs remained unaffected. This NPC biogenesis defect was not accompanied by a change in lipid composition. However, Brl1 interacted with Ndc1 and Nup188 by immunoprecipitation, and with transmembrane and outer and inner ring NPC components by split yellow fluorescent protein analysis, indicating a direct role in NPC biogenesis. Consistently, we found that Brr6 and Brl1 associated with a subpopulation of NPCs and emerging NPC assembly sites. Moreover, BRL1 overexpression affected NE morphology without a change in lipid composition and completely suppressed the nuclear pore biogenesis defect of nup116Δ and gle2Δ cells. We propose that Brr6 and Brl1 transiently associate with NPC assembly sites where they promote NPC biogenesis.

scholarly journals The transport of integral membrane proteins across the nuclear pore complex

Nucleus ◽  
2012 ◽  
Vol 3 (4) ◽  
pp. 322-329 ◽  
Author(s):  
Anne C. Meinema ◽  
Bert Poolman ◽  
Liesbeth M. Veenhoff
Keyword(s):  
Membrane Proteins ◽  
Nuclear Pore Complex ◽  
Integral Membrane Proteins ◽  
Nuclear Pore

scholarly journals The Torsin/ NEP1R1-CTDNEP1/ Lipin axis regulates nuclear envelope lipid metabolism for nuclear pore complex insertion

2020 ◽  
Author(s):  
Julie Jacquemyn ◽  
Joyce Foroozandeh ◽  
Katlijn Vints ◽  
Jef Swerts ◽  
Patrik Verstreken ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Nuclear Envelope ◽  
Nuclear Pore Complex ◽  
Lipid Droplets ◽  
Nuclear Pore ◽  
List Type ◽  
Unknown Mechanism ◽  
Structure Lipid ◽  
Cellular Events ◽  
Upstream Regulator

AbstractTorsin ATPases of the endoplasmic reticulum (ER) and nuclear envelope (NE) lumen inhibit Lipin-mediated phosphatidate (PA) to diacylglycerol (DAG) conversion by an unknown mechanism. This excess PA metabolism is implicated in TOR1A/TorsinA diseases, but it is unclear whether it explains why Torsin concomitantly affects nuclear structure, lipid droplets (LD), organelle and cell growth. Here a fly miniscreen identified that Torsins affect these events via the NEP1R1-CTDNEP1 phosphatase complex. Further, Torsin homo-oligomerization rather than ATPase activity was key to function. NEP1R1-CTDNEP1 activates Lipin by dephosphorylation. We show that Torsin prevents CTDNEP1 from accumulating in the NE and excludes Lipin from the nucleus. Moreover, this repression of nuclear PA metabolism is required for interphase nuclear pore biogenesis. We conclude that Torsin is an upstream regulator of the NEP1R1-CTDNEP1/ Lipin pathway. This connects the ER/NE lumen with PA metabolism, and affects numerous cellular events including it has a previously unrecognized role in nuclear pore biogenesis.HighlightsNuclear envelope PA-DAG-TAG synthesis is independently regulated by Torsin and Torip/LAP1Torsin removes CTDNEP1 from the nuclear envelope and excludes Lipin from the nucleusExcess nuclear envelope NEP1R1-CTDNEP1/ Lipin activity impairs multiple aspects of NPC biogenesisNEP1R1-CTDNEP1/ Lipin inhibition prevents cellular defects associated with TOR1A and TOR1AIP1 / LAP1 disease

From Signalosome to Enhanceosome: The Translocation of CD40 from Membrane to Nucleus Involves Multiple Mechanisms

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3781-3781
Author(s):  
Hai-Jun Zhou ◽  
Archie Tamayo ◽  
Lan Pham ◽  
Yen-Chiu Lin-Lee ◽  
Richard J. Ford
Keyword(s):  
Endoplasmic Reticulum ◽  
B Cell ◽  
B Lymphocytes ◽  
Nuclear Localization ◽  
Cell Nucleus ◽  
Nuclear Pore Complex ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Nuclear Pore ◽  
Lymphoma Cells

Abstract CD40 plays important roles in the proliferation, survival and differentiation of lymphocytes. Constitutively active CD40 recruits TRAFs and IKKs within the lipid rafts to form a signalosome that mediates pivotal downstream proliferation and survival mechanisms involving NF-kB. Recently, we have reported that nuclear localization of CD40, through its interaction with c-Rel, promotes growth, cell cycle progression and survival in large B cell lymphoma. Our studies have opened a new paradigm in the functional role of CD40 in non-Hodgkin lymphomas of B cell origin (NHL-B). However, the mechanism about how CD40 enters nuclear still remains elusive. In this study, we show that CD40 ligation enhances its nuclear accumulation with activation of c-Rel in both normal B-lymphocytes and B cell lymphoma cells with cell fractionation assay and con-focal microscopy. Over-expression of c-Rel in B cell lymphoma cells drives CD40 into cell nucleus. We hypothesize that the route CD40 enters nucleus may involve endosome-endoplasmic reticulum-nuclear pore complex. Indeed, further studies show CD40 co-localizes with endosome marker-EEA1 and endoplasmic reticulum marker-Sec61. Furthermore, our co-immunoprecipitation assay has demonstrated CD40 interacts with Sec61. CD40 also co-localizes and immuno-precipitates with nuclear pore complex (NPC) proteins-NUP62 in normal B-lymphocytes and B lymphoma cells, which suggests NPC proteins may facilitate the nuclear translocation of CD40 protein. Overall, our study suggests that translocation of CD40 into cell nucleus involves multiple pathways. Blocking nuclear localization may modulate the function of CD40 in lymphoma cells; which could provide a new-targeted therapeutic approach for lymphoma therapy.

scholarly journals Integral Membrane Proteins of the Nuclear Envelope Are Dispersed throughout the Endoplasmic Reticulum during Mitosis

1997 ◽  
Vol 137 (6) ◽  
pp. 1199-1210 ◽  
Author(s):  
Li Yang ◽  
Tinglu Guan ◽  
Larry Gerace
Keyword(s):  
Membrane Proteins ◽  
Nuclear Envelope ◽  
Nuclear Membrane ◽  
Mammalian Cells ◽  
Polyclonal Antibodies ◽  
Integral Membrane Proteins ◽  
Immunogold Electron Microscopy ◽  
Nuclear Pore ◽  
Nuclear Lamins ◽  
Nuclear Membranes

We have analyzed the fate of several integral membrane proteins of the nuclear envelope during mitosis in cultured mammalian cells to determine whether nuclear membrane proteins are present in a vesicle population distinct from bulk ER membranes after mitotic nuclear envelope disassembly or are dispersed throughout the ER. Using immunofluorescence staining and confocal microscopy, we compared the localization of two inner nuclear membrane proteins (laminaassociated polypeptides 1 and 2 [LAP1 and LAP2]) and a nuclear pore membrane protein (gp210) to the distribution of bulk ER membranes, which was determined with lipid dyes (DiOC6 and R6) and polyclonal antibodies. We found that at the resolution of this technique, the three nuclear envelope markers become completely dispersed throughout ER membranes during mitosis. In agreement with these results, we detected LAP1 in most membranes containing ER markers by immunogold electron microscopy of metaphase cells. Together, these findings indicate that nuclear membranes lose their identity as a subcompartment of the ER during mitosis. We found that nuclear lamins begin to reassemble around chromosomes at the end of mitosis at the same time as LAP1 and LAP2 and propose that reassembly of the nuclear envelope at the end of mitosis involves sorting of integral membrane proteins to chromosome surfaces by binding interactions with lamins and chromatin.

scholarly journals Characterization of constitutive ER-phagy of excess membrane proteins

PLoS Genetics ◽  
2020 ◽  
Vol 16 (12) ◽  
pp. e1009255
Author(s):  
Zhanna Lipatova ◽  
Valeriya Gyurkovska ◽  
Sarah F. Zhao ◽  
Nava Segev
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Membrane Proteins ◽  
Human Health ◽  
Mammalian Cells ◽  
Normal Growth ◽  
Integral Membrane Proteins ◽  
Yeast Cells ◽  
Cellular Proteins

Thirty percent of all cellular proteins are inserted into the endoplasmic reticulum (ER), which spans throughout the cytoplasm. Two well-established stress-induced pathways ensure quality control (QC) at the ER: ER-phagy and ER-associated degradation (ERAD), which shuttle cargo for degradation to the lysosome and proteasome, respectively. In contrast, not much is known about constitutive ER-phagy. We have previously reported that excess of integral-membrane proteins is delivered from the ER to the lysosome via autophagy during normal growth of yeast cells. Whereas endogenously expressed ER resident proteins serve as cargos at a basal level, this level can be induced by overexpression of membrane proteins that are not ER residents. Here, we characterize this pathway as constitutive ER-phagy. Constitutive and stress-induced ER-phagy share the basic macro-autophagy machinery including the conserved Atgs and Ypt1 GTPase. However, induction of stress-induced autophagy is not needed for constitutive ER-phagy to occur. Moreover, the selective receptors needed for starvation-induced ER-phagy, Atg39 and Atg40, are not required for constitutive ER-phagy and neither these receptors nor their cargos are delivered through it to the vacuole. As for ERAD, while constitutive ER-phagy recognizes cargo different from that recognized by ERAD, these two ER-QC pathways can partially substitute for each other. Because accumulation of membrane proteins is associated with disease, and constitutive ER-phagy players are conserved from yeast to mammalian cells, this process could be critical for human health.

scholarly journals Nuclear Envelope Proteins Modulating the Heterochromatin Formation and Functions in Fission Yeast

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1908 ◽  
Author(s):  
Yasuhiro Hirano ◽  
Haruhiko Asakawa ◽  
Takeshi Sakuno ◽  
Tokuko Haraguchi ◽  
Yasushi Hiraoka
Keyword(s):  
Endoplasmic Reticulum ◽  
Nuclear Envelope ◽  
Fission Yeast ◽  
Histone Deacetylase ◽  
Nuclear Pore Complex ◽  
Molecular Mechanisms ◽  
Nuclear Pore ◽  
Double Membrane ◽  
Heterochromatin Formation ◽  
Nuclear Membranes

The nuclear envelope (NE) consists of the inner and outer nuclear membranes (INM and ONM), and the nuclear pore complex (NPC), which penetrates the double membrane. ONM continues with the endoplasmic reticulum (ER). INM and NPC can interact with chromatin to regulate the genetic activities of the chromosome. Studies in the fission yeast Schizosaccharomyces pombe have contributed to understanding the molecular mechanisms underlying heterochromatin formation by the RNAi-mediated and histone deacetylase machineries. Recent studies have demonstrated that NE proteins modulate heterochromatin formation and functions through interactions with heterochromatic regions, including the pericentromeric and the sub-telomeric regions. In this review, we first introduce the molecular mechanisms underlying the heterochromatin formation and functions in fission yeast, and then summarize the NE proteins that play a role in anchoring heterochromatic regions and in modulating heterochromatin formation and functions, highlighting roles for a conserved INM protein, Lem2.

Biogenesis of tail-anchored proteins

2003 ◽  
Vol 31 (6) ◽  
pp. 1238-1242 ◽  
Author(s):  
N. Borgese ◽  
S. Brambillasca ◽  
P. Soffientini ◽  
M. Yabal ◽  
M. Makarow
Keyword(s):  
Amino Acids ◽  
Endoplasmic Reticulum ◽  
Membrane Proteins ◽  
Recent Work ◽  
Integral Membrane Proteins ◽  
Phospholipid Bilayer ◽  
Endoplasmic Reticulum Membrane ◽  
Regulatory Processes ◽  
C Terminus ◽  
Hydrophobic Amino Acids

A group of integral membrane proteins, known as C-tail anchored, is defined by the presence of a cytosolic N-terminal domain that is anchored to the phospholipid bilayer by a single segment of hydrophobic amino acids close to the C-terminus. The mode of insertion into membranes of these proteins, many of which play key roles in fundamental intracellular processes, is obligatorily post-translational, is highly specific and may be subject to regulatory processes that modulate the protein's function. Recent work has demonstrated that tail-anchored proteins translocate their C-termini across the endoplasmic reticulum membrane by a mechanism different from that used for Sec61-dependent post-translational signal-peptide-driven translocation. Here we summarize recent results on the insertion of tail-anchored proteins and discuss possible mechanisms that could be involved.

The protein translocation machinery of the endoplasmic reticulum

1982 ◽  
Vol 300 (1099) ◽  
pp. 225-228 ◽  
Keyword(s):  
Endoplasmic Reticulum ◽  
Membrane Proteins ◽  
Rough Endoplasmic Reticulum ◽  
Protein Translocation ◽  
Signal Sequence ◽  
Integral Membrane Proteins ◽  
Multiple Copies ◽  
And Function ◽  
Lysosomal Proteins

The rough endoplasmic reticulum (r.e.r.) has been postulated to possess a single translation-coupled translocation system (in multiple copies) that effects signal sequence-mediated translocation of all secretory and lysosomal proteins and integration of all integral membrane proteins whose port of entry is the rough endoplasmic reticulum (G. Blobel 1980 Proc. natn. Acad. Sci. U.S.A. 77, 1496—1500). Two proteins have been isolated that are components of the r.e.r. translocation system. Their properties and function in protein translocation across and integration into membranes are discussed.

scholarly journals Characterization of Constitutive macro-ER-phagy

2020 ◽  
Author(s):  
Zhanna Lipatova ◽  
Valeriya Gyurkovska ◽  
Sarah F. Zhao ◽  
Nava Segev
Keyword(s):  
Endoplasmic Reticulum ◽  
Membrane Proteins ◽  
Er Stress ◽  
Mammalian Cells ◽  
Normal Growth ◽  
Integral Membrane Proteins ◽  
Yeast Cells ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractThirty percent of all cellular proteins are inserted into the endoplasmic reticulum (ER), which spans throughout the cytoplasm. Two well-established stress-induced pathways ensure quality control (QC) at the ER: ER-phagy and ER-associated degradation (ERAD), which shuttle cargo for degradation to the lysosome and proteasome, respectively. In contrast, not much is known about constitutive ER-phagy. We have previously reported that excess of integral-membrane proteins is delivered from the ER to the lysosome via autophagy during normal growth of yeast cells. Here, we characterize this pathway as constitutive ER-phagy. Constitutive and stress-induced ER-phagy share the basic macro-autophagy machinery including the conserved Atgs and Ypt1 GTPase. However, induction of stress-induced autophagy is not needed for constitutive ER-phagy to occur. Moreover, the selective receptors needed for starvation-induced ER-phagy, Atg39 and Atg40, are not required for constitutive ER-phagy and neither these receptors nor their cargos are delivered through it to the vacuole. As for ERAD, while constitutive ER-phagy recognizes cargo different from that recognized by ERAD, these two ER-QC pathways can partially substitute for each other. Because accumulation of membrane proteins is associated with disease, and constitutive ER-phagy players are conserved from yeast to mammalian cells, this process could be critical for human health.Author SummaryAccumulation of excess proteins can lead to their aggregation, which in turn can cause multiple disorders, notably neurodegenerative disease. Nutritional and endoplasmic-reticulum (ER) stress stimulate autophagy and ER-associated degradation (ERAD) to clear excess and misfolded proteins, respectively. However, not much is known about clearance of excess proteins during normal growth. We have previously shown that excess integral-membrane proteins are cleared from the ER by macro-autophagy during normal growth of yeast cells. Here we characterize this pathway as constitutive ER-phagy. While this pathway shares machinery of core Atgs and autophagosomes with nutritional stress-induced ER-phagy, it differs from the latter: It is independent of the stress response and of receptors needed for stress-induced ER-phagy, and while stress-induced ER-phagy is not discriminatory, constitutive ER-phagy has specific cargos. However, when constitutive ER-phagy fails, machinery specific to stress-induced ER-phagy can process its cargo. Moreover, constitutive ER-phagy is also not dependent on ER-stress or the unfolded protein response (UPR) stimulated by this stress, although its failure elicits UPR. Finally, constitutive ER-phagy and ERAD can partially process each other’s cargo upon failure. In summary, constitutive ER-phagy, which clears excess integral-membrane proteins from the ER during normal growth does not require nutritional or ER stress for its function.

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