Uncoordinated (UNC)119: Coordinating the trafficking of myristoylated proteins

Constantine, Ryan; Zhang, Houbin; Gerstner, Cecilia D.; Frederick, Jeanne M.; Baehr, Wolfgang

doi:10.1016/j.visres.2012.08.012

Cited by 57 publications

(64 citation statements)

References 42 publications

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“…It is intriguing that the binding motif to Transducin α in the retina was mapped to the myristoylated N-terminal GAGASA sequence which strongly supports our interaction data with poly-GA [53]. Apart from this photoreceptor protein the only other known cargos in the nervous system are G α proteins in the C. elegans olfactory system [8]. It will be important to elucidate how Unc119 sequestration affects neuronal function in C9orf72 patients.…”

Section: Discussionsupporting

confidence: 56%

C9orf72 FTLD/ALS-associated Gly-Ala dipeptide repeat proteins cause neuronal toxicity and Unc119 sequestration

et al. 2014

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Hexanucleotide repeat expansion in C9orf72 is the most common pathogenic mutation in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite the lack of an ATG start codon, the repeat expansion is translated in all reading frames into dipeptide repeat (DPR) proteins, which form insoluble, ubiquitinated, p62-positive aggregates that are most abundant in the cerebral cortex and cerebellum. To specifically analyze DPR toxicity and aggregation, we expressed DPR proteins from synthetic genes containing a start codon but lacking extensive GGGGCC repeats. Poly-Gly-Ala (GA) formed p62-positive cytoplasmic aggregates, inhibited dendritic arborization and induced apoptosis in primary neurons. Quantitative mass spectrometry analysis to identify poly-GA co-aggregating proteins revealed a significant enrichment of proteins of the ubiquitin–proteasome system. Among the other interacting proteins, we identified the transport factor Unc119, which has been previously linked to neuromuscular and axonal function, as a poly-GA co-aggregating protein. Strikingly, the levels of soluble Unc119 are strongly reduced upon poly-GA expression in neurons, suggesting a loss of function mechanism. Similar to poly-GA expression, Unc119 knockdown inhibits dendritic branching and causes neurotoxicity. Unc119 overexpression partially rescues poly-GA toxicity suggesting that poly-GA expression causes Unc119 loss of function. In C9orf72 patients, Unc119 is detectable in 9.5 % of GA inclusions in the frontal cortex, but only in 1.6 % of GA inclusions in the cerebellum, an area largely spared of neurodegeneration. A fraction of neurons with Unc119 inclusions shows loss of cytosolic staining. Poly-GA-induced Unc119 loss of function may thereby contribute to selective vulnerability of neurons with DPR protein inclusions in the pathogenesis of C9orf72 FTLD/ALS.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-014-1329-4) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 56%

C9orf72 FTLD/ALS-associated Gly-Ala dipeptide repeat proteins cause neuronal toxicity and Unc119 sequestration

et al. 2014

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“…PDEd orthologs are highly conserved among vertebrates, invertebrates, and even unicellular organisms (Paramecium). A common ancestor of PDEd orthologs is the acyl-binding protein Uncoordinated (UNC) 119, the unc-119 homolog of C. elegans 64,105,135. …”

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confidence: 99%

Membrane Protein Transport in Photoreceptors: The Function of PDE

Baehr¹

2014

Investigative Ophthalmology & Visual Science

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This lecture details the elucidation of cGMP phosphodiesterase (PDEδ), discovered 25 years ago by Joe Beavo at the University of Washington. PDEδ, once identified as a fourth PDE6 subunit, is now regarded as a promiscuous prenyl-binding protein and important chaperone of prenylated small G proteins of the Ras superfamily and prenylated proteins of phototransduction. Alfred Wittinghofer's group in Germany showed that PDEδ forms an immunoglobulin-like β-sandwich fold that is closely related in structure to other lipid-binding proteins, for example, Uncoordinated 119 (UNC119) and RhoGDI. His group cocrystallized PDEδ with ARL (Arf-like) 2(GTP), and later with farnesylated Rheb (ras homolog expressed in brain). PDEδ specifically accommodates farnesyl and geranylgeranyl moieties in the absence of bound protein. Germline deletion of the Pde6d gene encoding PDEδ impeded transport of rhodopsin kinase (GRK1) and PDE6 to outer segments, causing slowly progressing, recessive retinitis pigmentosa. A rare PDE6D null allele in human patients, discovered by Tania Attié-Bitach in France, specifically impeded trafficking of farnesylated phosphatidylinositol 3,4,5-trisphosphate (PIP3) 5-phosphatase (INPP5E) to cilia, causing severe syndromic ciliopathy (Joubert syndrome). Binding of cargo to PDEδ is controlled by Arf-like proteins, ARL2 and ARL3, charged with guanosine-5'-triphosphate (GTP). Arf-like proteins 2 and 3 are unprenylated small GTPases that serve as cargo displacement factors. The lifetime of ARL3(GTP) is controlled by its GTPase-activating protein, retinitis pigmentosa protein 2 (RP2), which accelerates GTPase activity up to 90,000-fold. RP2 null alleles in human patients are associated with severe X-linked retinitis pigmentosa (XLRP). Germline deletion of RP2 in mouse, however, causes only a mild form of XLRP. Absence of RP2 prolongs the activity of ARL3(GTP) that, in turn, impedes PDE6δ-cargo interactions and trafficking of prenylated protein to the outer segments. Hyperactive ARL3(GTP), acting as a hyperactive cargo displacement factor, is predicted to be key in the pathobiology of RP2-XLRP.

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“…Based on these studies a model has been proposed where GSFs solubilise prenylated or myristoylated proteins aiding them to diffuse through the cytosol and at the point of destination Arl2 or Arl3 release the cargos [9,22,28]. For examples of GSF-cargo binding affinities and their release factors see table1.…”

Section: The Release Factorsmentioning

confidence: 99%

Shuttling and sorting lipid-modified cargo into the cilia

Stephen

Ismail

2016

Biochemical Society Transactions

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Primary cilia are hair-like microtubule-based organelles that can be found on almost all human cell types. Although the cilium is not separated from the cell by membranes, their content is different from that of the cell body and their membrane composition is distinct from that of the plasma membrane. Here we will introduce a molecular machinery that shuttles and sorts lipid modified proteins to the cilium, thus contributing in maintaining its distinct composition. The mechanism involves the binding of the GDI-like solubilising factors, UNC119a, UNC119b and PDE6D, to the lipid modified ciliary cargo and the specific release of the cargo in the cilia by the ciliary small G protein Arl3 in a GTP dependent manner.

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Uncoordinated (UNC)119: Coordinating the trafficking of myristoylated proteins

Cited by 57 publications

References 42 publications

C9orf72 FTLD/ALS-associated Gly-Ala dipeptide repeat proteins cause neuronal toxicity and Unc119 sequestration

C9orf72 FTLD/ALS-associated Gly-Ala dipeptide repeat proteins cause neuronal toxicity and Unc119 sequestration

Membrane Protein Transport in Photoreceptors: The Function of PDE

Shuttling and sorting lipid-modified cargo into the cilia

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