KLHL12-mediated ubiquitination of the dopamine D4 receptor does not target the receptor for degradation

Rondou, Pieter; Skieterska, Kamila; Packeu, Ann; Lintermans, Béatrice; Vanhoenacker, Peter; Vauquelin, Georges; Haegeman, Guy; Craenenbroeck, Kathleen Van

doi:10.1016/j.cellsig.2010.01.014

Cited by 28 publications

(16 citation statements)

References 47 publications

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“…The D4 receptor has been associated with attention deficit hyperactivity disorder and possesses an interesting polymorphism in its third intracellular loop. KLHL12, a BTB-Kelch protein, can specifically bind to this region and act as an adaptor to a Cullin 3-based E3 ubiquitin ligase, thus promoting polyubiquitination of the D4 receptor (Figure 4(d)) [72, 73]. Ubiquitination assays of D1, D5, and D2L show that DAR subtypes other than D4 can undergo basal ubiquitination, although KLHL12 appears to function solely as an adaptor for D4 ubiquitination [72].…”

Section: Ubiquitination Of Nonglutamate Receptorsmentioning

confidence: 99%

“…Ubiquitination assays of D1, D5, and D2L show that DAR subtypes other than D4 can undergo basal ubiquitination, although KLHL12 appears to function solely as an adaptor for D4 ubiquitination [72]. Further studies show that KLHL12 interacts with and promotes the ubiquitination of both immature ER-associated and mature plasma membrane-associated D4 receptors [73]. Surprisingly, experiments show that neither proteasomal ERAD degradation of new receptors nor lysosomal degradation of mature receptors occurs, an indication that GPCR ubiquitination may not always lead to degradation [73].…”

Section: Ubiquitination Of Nonglutamate Receptorsmentioning

confidence: 99%

“…Further studies show that KLHL12 interacts with and promotes the ubiquitination of both immature ER-associated and mature plasma membrane-associated D4 receptors [73]. Surprisingly, experiments show that neither proteasomal ERAD degradation of new receptors nor lysosomal degradation of mature receptors occurs, an indication that GPCR ubiquitination may not always lead to degradation [73]. Another study found that the D2 receptor subtype can be monoubiquitinated at lysine 241 in the absence of an agonist (Figure 4(d)).…”

Section: Ubiquitination Of Nonglutamate Receptorsmentioning

confidence: 99%

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Ubiquitination of Neurotransmitter Receptors and Postsynaptic Scaffolding Proteins

Lin

Man

2013

Neural Plasticity

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The human brain is made up of an extensive network of neurons that communicate by forming specialized connections called synapses. The amount, location, and dynamic turnover of synaptic proteins, including neurotransmitter receptors and synaptic scaffolding molecules, are under complex regulation and play a crucial role in synaptic connectivity and plasticity, as well as in higher brain functions. An increasing number of studies have established ubiquitination and proteasome-mediated degradation as universal mechanisms in the control of synaptic protein homeostasis. In this paper, we focus on the role of the ubiquitin-proteasome system (UPS) in the turnover of major neurotransmitter receptors, including glutamatergic and nonglutamatergic receptors, as well as postsynaptic receptor-interacting proteins.

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Section: Ubiquitination Of Nonglutamate Receptorsmentioning

confidence: 99%

Section: Ubiquitination Of Nonglutamate Receptorsmentioning

confidence: 99%

Section: Ubiquitination Of Nonglutamate Receptorsmentioning

confidence: 99%

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Ubiquitination of Neurotransmitter Receptors and Postsynaptic Scaffolding Proteins

Lin

Man

2013

Neural Plasticity

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“…In humans, most of the 52 BTB-BACK-Kelch proteins can be classified into two named groups, namely the 39 KLHL proteins and the 11 KBTBD proteins [7]–[9]. Notable proteins from this family include Keap1 (KLHL19), an electrophile-sensing regulator of Nrf2 [10]–[12], KLHL9, which is associated with an autosomal distal myopathy [13], KLHL12, a regulator of the dopamine D4 receptor [14] Dishevelled [15], [16] and CPOII coat function [17], KLHL20, a regulator of hypoxia-inducible factors [18], [19], and KLHL3, a regulator of hypertension with mutations identified in pseudohypoaldosteronism type II (PHAII) [20]–[22].…”

Section: Introductionmentioning

confidence: 99%

Crystal Structure of KLHL3 in Complex with Cullin3

Privé

2013

PLoS ONE

100

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KLHL3 is a BTB-BACK-Kelch family protein that serves as a substrate adapter in Cullin3 (Cul3) E3 ubiquitin ligase complexes. KLHL3 is highly expressed in distal nephron tubules where it is involved in the regulation of electrolyte homeostasis and blood pressure. Mutations in KLHL3 have been identified in patients with inherited hypertension disorders, and several of the disease-associated mutations are located in the presumed Cul3 binding region. Here, we report the crystal structure of a complex between the KLHL3 BTB-BACK domain dimer and two copies of an N terminal fragment of Cul3. We use isothermal titration calorimetry to directly demonstrate that several of the disease mutations in the KLHL3 BTB-BACK domains disrupt the association with Cul3. Both the BTB and BACK domains contribute to the Cul3 interaction surface, and an extended model of the dimeric CRL3 complex places the two E2 binding sites in a suprafacial arrangement with respect to the presumed substrate-binding sites.

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“…Several studies have reported that KLHL12 is a substrate adaptor of the CUL3 ubiquitin ligase complex, which can promote Dishevelled (Dsh) ubiquitination and degradation to negatively regulate the Wnt–β-catenin pathway (29). Moreover, the CUL3–KLHL12 ubiquitin ligase complex is known to monoubiquitinate SEC31 to regulate COPII vesicle coat formation (31), and can also promote polyubiquitination of the dopamine D4 receptor, but without causing degradation (30,36). Our results show that KHSRP, KLHL12 and CUL3 can form a complex to promote KHSRP ubiquitination (Figure 3), and this subsequently alters KHSRP regulation of EV71 IRES-driven translation.…”

Section: Discussionmentioning

confidence: 99%

Control of the negative IREStrans-acting factor KHSRP by ubiquitination

et al. 2016

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Cells and viruses can utilize internal ribosome entry sites (IRES) to drive translation when cap-dependent translation is inhibited by stress or viral factors. IRES trans-acting factors (ITAFs) are known to participate in such cap-independent translation, but there are gaps in the understanding as to how ITAFs, particularly negative ITAFs, regulate IRES-driven translation. This study found that Lys109, Lys121 and Lys122 represent critical ubiquitination sites for far upstream element-binding protein 2 (KHSRP, also known as KH-type splicing regulatory protein or FBP2), a negative ITAF. Mutations at these sites subsequently reduced KHSRP ubiquitination and abolished its inhibitory effect on IRES-driven translation. We further found that interaction between the Kelch domain of Kelch-like protein 12 (KLHL12) and the C-terminal domain of KHSRP contributed to KHSRP ubiquitination, leading to downregulation of enterovirus IRES-mediated translation in infected cells and increased competition against other positive ITAFs. Together, these results show that ubiquitination can exert control over IRES-driven translation via modification of ITAFs, and to the best of our knowledge, this is the first description of such a regulatory mechanism for IRES-dependent translation.

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KLHL12-mediated ubiquitination of the dopamine D4 receptor does not target the receptor for degradation

Cited by 28 publications

References 47 publications

Ubiquitination of Neurotransmitter Receptors and Postsynaptic Scaffolding Proteins

Ubiquitination of Neurotransmitter Receptors and Postsynaptic Scaffolding Proteins

Crystal Structure of KLHL3 in Complex with Cullin3

Control of the negative IREStrans-acting factor KHSRP by ubiquitination

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