KEL-8 Is a Substrate Receptor for CUL3-dependent Ubiquitin Ligase That Regulates Synaptic Glutamate Receptor Turnover

Schaefer, Henry; Rongo, Christopher

doi:10.1091/mbc.e05-08-0794

Cited by 77 publications

(78 citation statements)

References 65 publications

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“…If mutations in rab-10 or lin-10 result in the accumulation of GLR-1 at an internal membrane trafficking compartment, then these mutations should result in corresponding GLR-1-mediated behavioral phenotypes (Burbea et al, 2002;Juo and Kaplan, 2004;Shim et al, 2004;Umemura et al, 2005;Schaefer and Rongo, 2006). In C. elegans, GLR-1 signaling positively regulates spontaneous reversals during forward locomotion as animals forage for food (Mellem et al, 2002;Zheng et al, 2004).…”

Section: Mutations In Either Rab-10 or Lin-10 Results In Behavioral Phmentioning

confidence: 99%

“…18, November 2007 4389 (White et al, 1986;Kaplan and Horvitz, 1993). Mutants with reduced GLR-1 activity have a lower frequency of spontaneous reversals and are nose-touch insensitive, whereas mutants with increased GLR-1 activity (e.g., higher levels of synaptic GLR-1 at the cell surface) have a higher frequency of spontaneous reversals (Hart et al, 1995;Maricq et al, 1995;Burbea et al, 2002;Mellem et al, 2002;Juo and Kaplan, 2004;Shim et al, 2004;Zheng et al, 2004;Umemura et al, 2005;Schaefer and Rongo, 2006). We examined GLR-1-mediated behaviors in wild-type animals and in animals with mutations in lin-10 and rab-10.…”

Section: Rab-10 Regulates Glur Recyclingmentioning

confidence: 99%

“…Furthermore, GLR-1 is required at interneurons that are part of a simple sensory circuit regulating backward movement, both in response to nose-touch stimulus and as part of the foraging behavior of animals. Mutants with depressed GLR-1 synaptic levels are nosetouch defective and rarely reverse direction, whereas mutants with elevated synaptic levels reverse direction with increased frequency (Hart et al, 1995;Maricq et al, 1995;Zheng et al, 1999;Brockie et al, 2001b;Mellem et al, 2002;Schaefer and Rongo, 2006). Therefore, by observing the behavior (e.g., nose-touch response and reversals per minute) of animals with different genetic backgrounds, we can compare signal strength at this circuit, and we can infer the abundance of GLR-1 AMPARs present at the postsynaptic plasma membrane.…”

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confidence: 99%

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RAB-10 Regulates Glutamate Receptor Recycling in a Cholesterol-dependent Endocytosis Pathway

Glodowski

Chen

Schaefer

et al. 2007

MBoC

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104

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Regulated endocytosis of ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors (AMPARs) is critical for synaptic plasticity. However, the specific combination of clathrin-dependent and -independent mechanisms that mediate AMPAR trafficking in vivo have not been fully characterized. Here, we examine the trafficking of the AMPAR subunit GLR-1 in Caenorhabditis elegans. GLR-1 is localized on synaptic membranes, where it regulates reversals of locomotion in a simple behavioral circuit. Animals lacking RAB-10, a small GTPase required for endocytic recycling of intestinal cargo, are similar in phenotype to animals lacking LIN-10, a postsynaptic density 95/disc-large/zona occludensdomain containing protein: GLR-1 accumulates in large accretions and animals display a decreased frequency of reversals. Mutations in unc-11 (AP180) or itsn-1 (Intersectin 1), which reduce clathrin-dependent endocytosis, suppress the lin-10 but not rab-10 mutant phenotype, suggesting that LIN-10 functions after clathrin-mediated endocytosis. By contrast, cholesterol depletion, which impairs lipid raft formation and clathrin-independent endocytosis, suppresses the rab-10 but not the lin-10 phenotype, suggesting that RAB-10 functions after clathrin-independent endocytosis. Animals lacking both genes display additive GLR-1 trafficking defects. We propose that RAB-10 and LIN-10 recycle AMPARs from intracellular endosomal compartments to synapses along distinct pathways, each with distinct sensitivities to cholesterol and the clathrin-mediated endocytosis machinery. INTRODUCTIONContinuous movement of ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) into and out of synaptic membranes is a key mechanism for the regulation of excitatory synaptic strength. Previous work has shown that insertion of AMPARs into the plasma membrane strengthens synapses and that it is required to convert silent synapses into active synapses (Bredt and Nicoll, 2003;Malenka, 2003;Malinow, 2003;Sheng and Hyoung Lee, 2003;Gerges et al., 2005). Furthermore, it has recently been shown that recycling of AMPARs from internal endosomal compartments back to the plasma membrane is important for long-term potentiation (Park et al., 2004). By contrast, endocytosis of AMPARs at sites adjacent to the postsynaptic density is important for long-term depression (Carroll et al., 2001;Racz et al., 2004). Thus, molecular machinery required for endocytosis, as well as intracellular membrane trafficking processes, ultimately regulates the character of signal transmitted at each synapse.Multiple endocytosis trafficking pathways have been observed in cells. Clathrin-dependent endocytosis occurs at clathrin-coated pits, where transmembrane protein cargo and adaptor molecules recruit soluble clathrin (Le Roy and Wrana, 2005). Vesicles coated with a clathrin lattice are then pinched off from the membrane. Members of the Rab family of small guanosine triphosphate (GTP)ases mediate the intracellular membrane trafficking of endocytose...

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Section: Mutations In Either Rab-10 or Lin-10 Results In Behavioral Phmentioning

confidence: 99%

Section: Rab-10 Regulates Glur Recyclingmentioning

confidence: 99%

mentioning

confidence: 99%

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RAB-10 Regulates Glutamate Receptor Recycling in a Cholesterol-dependent Endocytosis Pathway

Glodowski

Chen

Schaefer

et al. 2007

MBoC

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104

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“…Schaefer and Rongo (71) reported that KEL-8 is involved in the degradation of glutamate receptors in neurons. However, KEL-8 did not directly interact with the glutamate receptors as the substrate adaptor.…”

Section: Discussionmentioning

confidence: 99%

Control of Rapsyn Stability by the CUL-3-containing E3 Ligase Complex

Nam

Min

Hwang

et al. 2009

Journal of Biological Chemistry

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Rapsyn is a postsynaptic protein required for clustering of nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction. Here we report the mechanism for posttranslational control of rapsyn protein stability. We confirmed that C18H9.7-encoded RPY-1 is a rapsyn homolog in Caenorhabditis elegans by showing that human rapsyn rescued rpy-1 mutant phenotypes in nematodes, as determined by levamisole assays and micropost array behavioral assays. We found that RPY-1 was degraded in the absence of functional UNC-29, a non-␣ subunit of the receptor, in an allele-specific manner, but not in the absence of other receptor subunits. The cytoplasmic loop of UNC-29 was found to be critical for RPY-1 stability. Through RNA interference screening, we found that UBC-1, UBC-12, NEDD-8, and RBX-1 were required for degradation of RPY-1. We identified cullin (CUL)-3 as a component of E3 ligase and KEL-8 as the substrate adaptor of RPY-1. Mammalian rapsyn was ubiquitinated by the CUL3/KLHL8-containing E3 ligase in vitro, and the knockdown of KLHL-8, a mammalian KEL-8 homolog, inhibited rapsyn ubiquitination in vivo, implying evolutionary conservation of the rapsyn stability control machinery. kel-8 suppression and rpy-1 overexpression in C. elegans produced a phenotype similar to that of a loss-of-function mutation of rpy-1, suggesting that control of rapsyn abundance is important for proper function of the receptor. Our results suggest a link between the control of rapsyn abundance and congenital myasthenic syndromes.

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“…The UPS has been shown to regulate GluR synaptic abundance both directly and indirectly. In C. elegans, direct ubiquitination and proteasomal degradation of GluR1 subunits has been demonstrated (Burbea et al, 2002), but the UPS also indirectly regulates GluR1 synaptic abundance through multiple other pathways (Juo and Kaplan, 2004;Dreier et al, 2005;Schaefer and Rongo, 2006). In cultured rat hippocampal neurons, indirect regulation of AMPA receptors has been demonstrated through ubiquitination and degradation of the postsynaptic scaffolding protein PSD-95 (Colledge et al, 2003), and agonist-induced AMPA receptor internalization has been shown to be dependent on UPSmediated degradation of an undetermined synaptic protein (Patrick et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

The ubiquitin–proteasome system postsynaptically regulates glutamatergic synaptic function

Haas

Miller

Friedman

et al. 2007

Molecular and Cellular Neuroscience

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The ubiquitin proteasome system (UPS) actively controls protein dynamics and local abundance via regulated protein degradation. This study investigates UPS roles in the regulation of postsynaptic function and molecular composition in the Drosophila neuromuscular junction (NMJ) genetic system. To specifically impair UPS function postsynaptically, the UAS/GAL4 transgenic method was employed to drive postsynaptic expression of proteasome β2 and β6 subunit mutant proteins, which operate through a dominant negative mechanism to block proteasome function. When proteasome mutant subunits were constitutively expressed, excitatory junctional current (EJC) amplitudes were increased, demonstrating that postsynaptic proteasome function limits neurotransmission strength. Interestingly, the alteration in synaptic strength was calcium-dependent and miniature EJCs had significantly smaller mean amplitudes and more rapid mean decay rates. Postsynaptic levels of the Drosophila PSD-95/SAP97 homologue, discs large (DLG), and the GluRIIB-containing glutamate receptor were increased, but GluRIIA-containing receptors were unaltered. With acute postsynaptic proteasome inhibition using an inducible transgenic system, neurotransmission was similarly elevated with the same specific increase in postsynaptic GluRIIB abundance. These findings demonstrate postsynaptic proteasome regulation of glutamatergic synaptic function that is mediated through specific regulation of GluRIIB-containing glutamate receptors.

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KEL-8 Is a Substrate Receptor for CUL3-dependent Ubiquitin Ligase That Regulates Synaptic Glutamate Receptor Turnover

Cited by 77 publications

References 65 publications

RAB-10 Regulates Glutamate Receptor Recycling in a Cholesterol-dependent Endocytosis Pathway

RAB-10 Regulates Glutamate Receptor Recycling in a Cholesterol-dependent Endocytosis Pathway

Control of Rapsyn Stability by the CUL-3-containing E3 Ligase Complex

The ubiquitin–proteasome system postsynaptically regulates glutamatergic synaptic function

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