Altered palmitoylation and neuropathological deficits in mice lacking HIP14

Singaraja, Roshni R.; Huang, Kun; Sanders, Shaun S.; Milnerwood, Austen J.; Hines, Rochelle M.; Lerch, Jason P.; Franciosi, Sonia; Drisdel, Renaldo C.; Vaid, Kuljeet; Young, Fiona B.; Doty, Crystal N.; Wan, Junmei; Bissada, Nagat; Henkelman, R. Mark; Green, William N.; Davis, Nicholas G.; Raymond, Lynn A.; Hayden, Michael R.

doi:10.1093/hmg/ddr308

Cited by 108 publications

(165 citation statements)

References 36 publications

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“…34,56 Taken together, our data show that CASP6 is palmitoylated by the PAT HIP14 and that cysteines 264 and 277 are the main sites of palmitoylation.…”

Section: Discussionsupporting

confidence: 54%

“…ns, not significant CASP6 palmitoylation is decreased in STHdhQ111 cells and in the YAC128 HD mouse brain. As HIP14 is dysfunctional in the presence of mutant HTT in YAC128 mice, 34 we assessed the levels of palmitoylation of CASP6 in the brains from YAC128 mice, as well as in the HD cell model STHdhQ111 of striatal origin. 42 Indeed, the palmitoylation of CASP6 was significantly decreased by~15% in the YAC128 brains (Figure 2a).…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, we previously showed that the palmitoyl acyltransferase (PAT) HIP14 (DHHC17) is dysfunctional in the presence of mutant HTT in the YAC128 mice and displays a reduced ability to transfer palmitate to its substrates, 34 suggesting that altered palmitoylation of HIP14 substrates could contribute to the pathogenesis of HD. This is further supported by our recent work demonstrating a significant association between palmitoylation and HD in a curated list of palmitoylated proteins 35 and by the finding that mice with a targeted disruption of the Hip14 gene display HD-like phenotypes.…”

mentioning

confidence: 99%

“…This is further supported by our recent work demonstrating a significant association between palmitoylation and HD in a curated list of palmitoylated proteins 35 and by the finding that mice with a targeted disruption of the Hip14 gene display HD-like phenotypes. 34 S-palmitoylation (here referred to simply as palmitoylation) is the reversible, posttranslational covalent attachment of palmitic acid to cysteine residues of proteins via a thioester bond. 36 Palmitoylation increases the hydrophobicity of proteins and thereby regulates membrane association, subcellular localization, 36 and enzyme function and activity.…”

mentioning

confidence: 99%

“…36 Palmitoylation increases the hydrophobicity of proteins and thereby regulates membrane association, subcellular localization, 36 and enzyme function and activity. 37,38 As CASP6 activation and reduced palmitoylation of HIP14 substrates are both associated with phenotypes in HD, 18,34 we investigated whether CASP6 is palmitoylated and whether palmitoylation regulates its activation.…”

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confidence: 99%

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Palmitoylation of caspase-6 by HIP14 regulates its activation

et al. 2016

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Caspase-6 (CASP6) has an important role in axonal degeneration during neuronal apoptosis and in the neurodegenerative diseases Alzheimer and Huntington disease. Decreasing CASP6 activity may help to restore neuronal function in these and other diseases such as stroke and ischemia, where increased CASP6 activity has been implicated. The key to finding approaches to decrease CASP6 activity is a deeper understanding of the mechanisms regulating CASP6 activation. We show that CASP6 is posttranslationally palmitoylated by the palmitoyl acyltransferase HIP14 and that the palmitoylation of CASP6 inhibits its activation. Palmitoylation of CASP6 is decreased both in Hip14 −/− mice, where HIP14 is absent, and in YAC128 mice, a model of Huntington disease, where HIP14 is dysfunctional and where CASP6 activity is increased. Molecular modeling suggests that palmitoylation of CASP6 may inhibit its activation via steric blockage of the substrate-binding groove and inhibition of CASP6 dimerization, both essential for CASP6 function. Our studies identify palmitoylation as a novel CASP6 modification and as a key regulator of CASP6 activity.

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“…34,56 Taken together, our data show that CASP6 is palmitoylated by the PAT HIP14 and that cysteines 264 and 277 are the main sites of palmitoylation.…”

Section: Discussionsupporting

confidence: 54%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Palmitoylation of caspase-6 by HIP14 regulates its activation

et al. 2016

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Smarter neuronal signaling complexes from existing components: How regulatory modifications were acquired during animal evolution

Thomas

Hayashi

2013

BioEssays

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Neurons of organisms with complex and flexible behavior, especially humans, must precisely control protein localization and activity to support higher brain functions such as learning and memory. In contrast, simpler organisms generally have simpler individual neurons, less complex nervous systems and display more limited behaviors. Strikingly, however, many key neuronal proteins are conserved between organisms that have very different degrees of behavioral complexity. Here we discuss a possible mechanism by which conserved neuronal proteins acquired new attributes that were crucial in the evolution of complexity of nervous system structure and function. Specifically, we hypothesize that vertebrate-specific post-translational palmitoylation sites and PDZ-binding protein-protein interaction motifs act as gain-of-function mutations, increasing the regulatory potential of conserved proteins without affecting their core functions. We further hypothesize that the additional regulation of neurotransmitter receptors and other membrane proteins made possible by these sites and motifs is critical for the function of complex nervous systems.

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ZDHHC16 modulates FGF/ERK dependent proliferation of neural stem/progenitor cells in the zebrafish telencephalon

Shi

Chen

Wang

et al. 2016

Developmental Neurobiology

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In vertebrates, neural stem/progenitor cells (NSPCs) maintenance is critical for nervous system development and homeostasis. However, the molecular mechanisms underlying the maintenance of NSPCs have not been fully elucidated. Here, we demonstrated that zebrafish ZDHHC16, a DHHC encoding protein, which was related to protein palmitoylation after translation, was expressed in the developing forebrain, and especially in the telencephalon. Loss- and gain-of-function studies showed that ZDHHC16 played a crucial role in the regualtion of NSPCs proliferation during zebrafish telencephalic development, via a mechanism dependent on its palmitoyltransferase activity. Further analyses showed that the inhibition of ZDHHC16 led to inactivation of the FGF/ERK signaling pathway during telencephalic NSPCs proliferation and maintenance. Taken together, our results suggest that ZDHHC16 activity is essential for early NSPCs proliferation where it acts to activate the FGF/ERK network, allowing for the initiation of proliferation -regulated gene expression programs. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 76: 1014-1028, 2016.

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Altered palmitoylation and neuropathological deficits in mice lacking HIP14

Cited by 108 publications

References 36 publications

Palmitoylation of caspase-6 by HIP14 regulates its activation

Palmitoylation of caspase-6 by HIP14 regulates its activation

Smarter neuronal signaling complexes from existing components: How regulatory modifications were acquired during animal evolution

ZDHHC16 modulates FGF/ERK dependent proliferation of neural stem/progenitor cells in the zebrafish telencephalon

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