SEL‐10 interacts with presenilin 1, facilitates its ubiquitination, and alters A‐beta peptide production

Li, Jinhe; Pauley, Adele M.; Myers, Rick L.; Shuang, Rongqing; Brashler, John R.; Yan, Riqiang; Buhl, Allen E.; Ruble, Cara; Gurney, Mark E.

doi:10.1046/j.1471-4159.2002.01105.x

Cited by 62 publications

(43 citation statements)

References 50 publications

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“…The interaction between SEL-10 and SEL-12, therefore, might differ from other SEL-10-substrate interactions, a difference that may be evolutionarily conserved in the interaction of the homologous proteins hSEL-10 and PS1 in Alzheimer's disease (32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

“…The SEL-10 protein can interact with the intracellular domain of the LIN-12 protein in mammalian cells (17), and mammalian SEL-10 interacts with the intracellular domain of mammalian Notch, N IC , targeting it for ubiquitinmediated degradation (24,30,31). SEL-10 also appears to be a negative regulator of the presenilin SEL-12, and mammalian SEL-10 targets the presenilin PS1, which has been implicated in Alzheimer's disease, for degradation (32)(33)(34). SEL-10 contains eight WD40 repeats, which are located in the C-terminal half of the protein (17,35).…”

Section: All Eight Independently Isolated Egl-41 (Gf) Mutants Carry Amentioning

confidence: 99%

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The Caenorhabditis elegans F-box protein SEL-10 promotes female development and may target FEM-1 and FEM-3 for degradation by the proteasome

Jäger

Schwartz²,

Horvitz³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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The Caenorhabditis elegans F-box protein SEL-10 and its human homolog have been proposed to regulate LIN-12 Notch signaling by targeting for ubiquitin-mediated proteasomal degradation LIN-12 Notch proteins and SEL-12 PS1 presenilins, the latter of which have been implicated in Alzheimer's disease. We found that sel-10 is the same gene as egl-41, which previously had been defined by gain-of-function mutations that semidominantly cause masculinization of the hermaphrodite soma. Our results demonstrate that mutations causing loss-of-function of sel-10 also have masculinizing activity, indicating that sel-10 functions to promote female development. Genetically, sel-10 acts upstream of the genes fem-1, fem-2, and fem-3 and downstream of her-1 and probably tra-2. When expressed in mammalian cells, SEL-10 protein coimmunoprecipitates with FEM-1, FEM-2, and FEM-3, which are required for masculinization, and FEM-1 and FEM-3 are targeted by SEL-10 for proteasomal degradation. We propose that SEL-10-mediated proteolysis of FEM-1 and FEM-3 is required for normal hermaphrodite development.C aenorhabditis elegans develops either as a self-fertilizing XX hermaphrodite or as an X0 male (1). The X-to-autosome (X͞A) ratio provides the primary sex-determining signal and specifies the activity of her (hermaphrodization)-1. Downstream of her-1, five genes [tra (transformer)-2, tra-3, fem ( feminization)-1, fem-2, and fem-3] control the activity of tra-1, the terminal, global regulator of somatic sexual fate. In XX animals, the her-1 gene, which encodes a secreted protein, is not expressed (2). The lack of her-1 expression in XX animals permits the activation of the transmembrane protein TRA-2, which blocks the functions of FEM-1 (a novel protein) (3), FEM-2 (a type 2C protein phosphatase) (4, 5), and FEM-3 (an ankyrin-repeat protein) (6), possibly by interacting directly with FEM-3 (7). This block leads to the activation of the Zn-finger DNA-binding protein TRA-1 (8). Active TRA-1 represses the transcription of genes required for male development, resulting in the formation of an animal with a female soma: a hermaphrodite (9, 10). In X0 animals, the HER-1 protein is present and inhibits TRA-2 (11, 12). The FEM proteins are, thus, relieved from negative regulation by TRA-2, resulting in the FEM-dependent inhibition of TRA-1 and subsequent male development.The gene egl (egg-laying-defective)-41 was defined by three semidominantly acting mutations, n1069, n1074, and n1077, which were identified in a screen for egg-laying-defective (Egl) hermaphrodites (13). Additional egl-41 alleles were identified in screens for mutations that suppress a semidominantly acting tra-2 mutation (e2055) (14), which cause the male-specific cephalic companion neurons (CEMs) to survive in hermaphrodites (n3717; H.T.S. and H.R.H., unpublished data) or that cause abnormalities in the sex-specific pattern of cell deaths in the ventral cord (n3854, n4041, and n4046; B. Galvin and H.R.H., unpublished results). egl-41 hermaphrodites are weakly masculinized; for exa...

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Section: Discussionmentioning

confidence: 99%

Section: All Eight Independently Isolated Egl-41 (Gf) Mutants Carry Amentioning

confidence: 99%

The Caenorhabditis elegans F-box protein SEL-10 promotes female development and may target FEM-1 and FEM-3 for degradation by the proteasome

Jäger

Schwartz²,

Horvitz³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…Ubiquitylation and proteasome-mediated degradation are responsible for removal of many proteins (30) and may operate on other proteins in the ␥-secretase complex, including PS1. Support for this notion comes from the observation that PS1 levels are strongly reduced in the absence of nicastrin or Aph-1 and that PS can be ubiquitylated by the mammalian Sel-10 E3 ubiquitin ligase (31), which also ubiquitylates Notch (27).…”

Section: Discussionmentioning

confidence: 99%

Pen-2 Is Sequestered in the Endoplasmic Reticulum and Subjected to Ubiquitylation and Proteasome-mediated Degradation in the Absence of Presenilin

Bergman

Hansson

Pursglove

et al. 2004

Journal of Biological Chemistry

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The ␥-secretase complex catalyzes intramembrane proteolysis of a number of transmembrane proteins, including amyloid precursor protein, Notch, ErbB4, and E-cadherin. ␥-Secretase is known to contain four major protein constituents: presenilin (PS), nicastrin, Aph-1, and Pen-2, all of which are integral membrane proteins. There is increasing evidence that the formation of the complex and the stability of the individual components are tightly controlled in the cell, assuring correct composition of functional complexes. In this report, we investigate the topology, localization, and mechanism for destabilization of Pen-2 in relation to PS function. We show that PS1 regulates the subcellular localization of Pen-2: in the absence of PS, Pen-2 is sequestered in the endoplasmic reticulum (ER) and not transported to post-ER compartments, where the mature ␥-secretase complexes reside. PS deficiency also leads to destabilization of Pen-2, which is alleviated by proteasome inhibitors. In keeping with this, we show that Pen-2, which adopts a hairpin structure with the N and C termini facing the luminal space, is ubiquitylated prior to degradation and presumably retrotranslocated from the ER to the cytoplasm. Collectively, our data suggest that failure to become incorporated into the ␥-secretase complex leads to degradation of Pen-2 through the ER-associated degradation-proteasome pathway.

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“…SEL-10 was identified as a down regulator of LIN-12 in C. elegans, and was shown to act through ubiquitin-mediated proteasomal degradation (Hubbard et al 1997;Wu et al 2001;Li et al 2002). SEL-10 is a member of the family of Fbw7 proteins (F-box and WD repeat domain-containing 7) that includes the yeast and human Cdc4 proteins (reviewed in Welcker and Clurman 2008).…”

mentioning

confidence: 99%

“…Loss-of-function mutations in Fbw7 genes are associated with tumorigenesis, as Fbw7 substrates become inappropriately stabilized (Welcker and Clurman 2008). Studies in both C. elegans and mammals have established presenilin and the Notch intracellular domain as direct targets of the SEL-10 Fbw7 protein, which promotes their ubiquitination and proteasomal degradation (Hubbard et al 1997;Wu et al 1998;Wu et al 2001;Gupta-Rossi et al 2001;Li et al 2002); however, such a role for SEL-10 in the embryo has not yet been explored. Genetic interactions between C. elegans sel-10 and genes of the sex-determination pathway point to additional targets of SEL-10-mediated downregulation (Jager et al 2004), making the study of sel-10 throughout C. elegans development a useful model system in which to analyze the dynamic function of Fbw7 proteins.…”

mentioning

confidence: 99%

Notch Signaling Is Antagonized by SAO-1, a Novel GYF-Domain Protein That Interacts with the E3 Ubiquitin Ligase SEL-10 in Caenorhabditis elegans

et al. 2012

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Notch signaling pathways can be regulated through a variety of cellular mechanisms, and genetically compromised systems provide useful platforms from which to search for the responsible modulators. The Caenorhabditis elegans gene aph-1 encodes a component of g-secretase, which is essential for Notch signaling events throughout development. By looking for suppressors of the incompletely penetrant aph-1(zu147) mutation, we identify a new gene, sao-1 (suppressor of aph-one), that negatively regulates aph-1(zu147) activity in the early embryo. The sao-1 gene encodes a novel protein that contains a GYF protein-protein interaction domain and interacts specifically with SEL-10, an Fbw7 component of SCF E3 ubiquitin ligases. We demonstrate that the embryonic lethality of aph-1(zu147) mutants can be suppressed by removing sao-1 activity or by mutations that disrupt the SAO-1-SEL-10 protein interaction. Decreased sao-1 activity also influences Notch signaling events when they are compromised at different molecular steps of the pathway, such as at the level of the Notch receptor GLP-1 or the downstream transcription factor LAG-1. Combined analysis of the SAO-1-SEL-10 protein interaction and comparisons of sao-1 and sel-10 genetic interactions suggest a possible role for SAO-1 as an accessory protein that participates with SEL-10 in downregulation of Notch signaling. This work provides the first mutant analysis of a GYF-domain protein in either C. elegans or Drosophila and introduces a new type of Fbw7-interacting protein that acts in a subset of Fbw7 functions.

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SEL‐10 interacts with presenilin 1, facilitates its ubiquitination, and alters A‐beta peptide production

Cited by 62 publications

References 50 publications

The Caenorhabditis elegans F-box protein SEL-10 promotes female development and may target FEM-1 and FEM-3 for degradation by the proteasome

The Caenorhabditis elegans F-box protein SEL-10 promotes female development and may target FEM-1 and FEM-3 for degradation by the proteasome

Pen-2 Is Sequestered in the Endoplasmic Reticulum and Subjected to Ubiquitylation and Proteasome-mediated Degradation in the Absence of Presenilin

Notch Signaling Is Antagonized by SAO-1, a Novel GYF-Domain Protein That Interacts with the E3 Ubiquitin Ligase SEL-10 in Caenorhabditis elegans

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