Inhibition of Metabotropic Glutamate Receptor Signaling by the Huntingtin-binding Protein Optineurin

Abstract

Huntington disease is caused by a polyglutamine expansion in the huntingtin protein (Htt) and is associated with excitotoxic death of striatal neurons. Group I metabotropic glutamate receptors (mGluRs) that are coupled to inositol 1,4,5-triphosphate formation and the release of intracellular Ca 2؉ stores play an important role in regulating neuronal function. We show here that mGluRs interact with the Htt-binding protein optineurin that is also linked to normal pressure open angled glaucoma and, when expressed in HEK 293 cells, optineurin functions to antagonize agonist-stimulated mGluR1a signaling. We find that Htt is co-precipitated with mGluR1a and that mutant Htt functions to facilitate optineurinmediated attenuation of mGluR1a signaling. In striatal cell lines derived from Htt Q111/Q111 mutant knock-in mice mGluR5-stimulated inositol phosphate formation is also severely impaired when compared with striatal cells derived from Htt Q7/Q7 knock-in mice. In addition, we show that a missense single nucleotide polymorphism optineurin H486R variant previously identified to be associated with glaucoma is selectively impaired in mutant Htt binding. Although optineurin H486R retains the capacity to bind to mGluR1a, optineurin H486R-dependent attenuation of mGluR1a signaling is not enhanced by the expression of mutant Htt. Because G protein-coupled receptor kinase 2 (GRK2) protein expression is relatively low in striatal tissue, we propose that optineurin may substitute for GRK2 in the striatum to mediate mGluR desensitization. Taken together, these studies identify a novel mechanism for mGluR desensitization and an additional biochemical link between altered glutamate receptor signaling and Huntington disease. Huntington disease (HD)4 is an autosomal-dominant neurodegenerative disorder manifested by symptoms of involuntary body movement, loss of cognitive function, and psychiatric disturbance, which inevitably leads to death (1-4). The HD gene mutation consists of an unstable CAG repeat resulting in a polyglutamine expansion in the amino-terminal region of the huntingtin (Htt) protein, a ubiquitously expressed and evolutionary conserved protein (1). It is the polyglutamine expansion of the Htt amino terminus that is proposed to cause progressive widespread neuronal death in the neocortex and the striatum of HD patients. Although the precise function of Htt in cells is not completely understood, analysis of the proteins with which Htt interacts suggests that Htt plays a role in regulating clathrin-coated vesicle-mediated endocytosis, neuronal survival, vesicle transport, morphogenesis, calcium homeostasis, and transcriptional regulation (4).Glutamate-mediated neurotoxicity has been postulated to play an important role in the pathogenesis and excitotoxic neuronal cell loss in HD (5-9). The receptors for glutamate are classified into two types: ionotropic and metabotropic (10). The ionotropic receptors comprise cation-specific ion channels that mediate fast excitatory glutamate responses and are subdivided into AMPA/kain...

Toward an integrative view of Optineurin functions

“…18,79 Interaction between Optn and a mutated form of Htt (namely Htt Q138 ) is impaired by mutation of the Ub-binding domain of Optn. 80 Furthermore, mutated Htt that is still able to interact with Optn, delocalized Optn and Rab8 from the Golgi apparatus to the cytosol and impaired post-Golgi trafficking to the plasma membrane and to the lysosomes. 24,80 The ubiquitin-binding function of Optn is also important for antiviral immune response, selective autophagy of cytosolic bacteria and Transferrin receptor (TfR) recycling.…”

“…80 Furthermore, mutated Htt that is still able to interact with Optn, delocalized Optn and Rab8 from the Golgi apparatus to the cytosol and impaired post-Golgi trafficking to the plasma membrane and to the lysosomes. 24,80 The ubiquitin-binding function of Optn is also important for antiviral immune response, selective autophagy of cytosolic bacteria and Transferrin receptor (TfR) recycling. 43,55,78 However, the role of Ub-binding activity in some Optn-mediated functions, such as the transport of lysosomal proteins, remains to be determined.…”

Metabotropic Glutamate Receptor-Mediated Cell Signaling Pathways Are Altered in a Mouse Model of Huntington's Disease

“…Recently, we determined that group I mGluRs interact with mutant Htt and that mGluR5 signaling was selectively uncoupled as a consequence of this interaction (Anborgh et al, 2005). Thus, it is possible that alterations of receptor-mediated signaling pathways could con-tribute to protection or exacerbation of cell death cascades in the symptomatic and/or presymptomatic phases of HD.…”

A quantitative trait locus for variation in dopamine metabolism mapped in a primate model using reference sequences from related species

“…There are no obvious candidate genes within the HVA QTL, based on the criterion of a known direct involvement in dopamine metabolism, but several genes in this region could contribute to pathways involved in its regulation. The peak of the QTL (between SNPs DHs36-12 and DHs48-08-6, at locations 10.5 and 14.4 Mb, respectively) includes genes for huntingtininteracting protein, optineurin, which contributes to metabotropic glutamate receptor desensitization (38), and CUGBP2. The latter gene regulates alternative splicing of several known In the region between Ϸ7.5 and Ϸ17.5 Mb (dashed lines), where the highest lod scores are found, low lod scores were found primarily for uninformative SNPs with high homozygosity.…”