ELP3 Controls Active Zone Morphology by Acetylating the ELKS Family Member Bruchpilot

Miśkiewicz, Katarzyna; Jose, Liya; Bento‐Abreu, André; Fislage, Marcus; Taes, Ines; Kasprowicz, Jarosław; Swerts, Jef; Sigrist, Stephan J.; Versées, Wim; Robberecht, Wim; Verstreken, Patrik

doi:10.1016/j.neuron.2011.10.010

Cited by 95 publications

(77 citation statements)

References 54 publications

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“…However, the regulatory effect of the elongator complex on ␣-tubulin acetylation is controversial. Recent research showed that a deficiency in ELP3, which is the catalytic subunit of elongator complex, did not decrease the level of ␣-tubulin acetylation in cell lines and cortical neurons (Mioekiewicz et al, 2011). Whether ␣-tubulin acetylation underlies the migratory defect in ELP3-deficient neurons needs to be further clarified.…”

Section: Discussionmentioning

confidence: 99%

MEC-17 Deficiency Leads to Reduced α-Tubulin Acetylation and Impaired Migration of Cortical Neurons

Wei

Wang

et al. 2012

J. Neurosci.

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Neuronal migration is a fundamental process during the development of the cerebral cortex and is regulated by cytoskeletal components. Microtubule dynamics can be modulated by posttranslational modifications to tubulin subunits. Acetylation of ␣-tubulin at lysine 40 is important in regulating microtubule properties, and this process is controlled by acetyltransferase and deacetylase. MEC-17 is a newly discovered ␣-tubulin acetyltransferase that has been found to play a major role in the acetylation of ␣-tubulin in different species in vivo. However, the physiological function of MEC-17 during neural development is largely unknown. Here, we report that MEC-17 is critical for the migration of cortical neurons in the rat. MEC-17 was strongly expressed in the cerebral cortex during development. MEC-17 deficiency caused migratory defects in the cortical projection neurons and interneurons, and perturbed the transition of projection neurons from the multipolar stage to the unipolar/bipolar stage in the intermediate zone of the cortex. Furthermore, knockdown of ␣-tubulin deacetylase HDAC6 or overexpression of tubulin K40Q to mimic acetylated ␣-tubulin could reduce the migratory and morphological defects caused by MEC-17 deficiency in cortical projection neurons. Thus, MEC-17, which regulates the acetylation of ␣-tubulin, appears to control the migration and morphological transition of cortical neurons. This finding reveals the importance of MEC-17 and ␣-tubulin acetylation in cortical development.

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Section: Discussionmentioning

confidence: 99%

MEC-17 Deficiency Leads to Reduced α-Tubulin Acetylation and Impaired Migration of Cortical Neurons

Wei

Wang

et al. 2012

J. Neurosci.

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“…The elongator complex comprises six proteins, ELP1-6, and is responsible both for histone acetylation to facilitate transcription and for the modification of the wobble position U-34 of eukaryotic tRNAs by carbamoylmethylation or methoxy-carbonylmethylation at C-5 of uridine (35,36). ELP3 contains both radical SAM and histone acetyltransferase domains.…”

Section: Discussionmentioning

confidence: 99%

Does Viperin Function as a Radical S-Adenosyl-l-methionine-dependent Enzyme in Regulating Farnesylpyrophosphate Synthase Expression and Activity?

Makins

Ghosh²,

Román‐Meléndez³

et al. 2016

Journal of Biological Chemistry

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Edited by Charles SamuelViperin is an endoplasmic reticulum-associated antiviral responsive protein that is highly up-regulated in eukaryotic cells upon viral infection through both interferon-dependent and independent pathways. Viperin is predicted to be a radical S-adenosyl-L-methionine (SAM) enzyme, but it is unknown whether viperin actually exploits radical SAM chemistry to exert its antiviral activity. We have investigated the interaction of viperin with its most firmly established cellular target, farnesyl pyrophosphate synthase (FPPS). Numerous enveloped viruses utilize cholesterol-rich lipid rafts to bud from the host cell membrane, and it is thought that by inhibiting FPPS activity (and therefore cholesterol synthesis), viperin retards viral budding from infected cells. We demonstrate that, consistent with this hypothesis, overexpression of viperin in human embryonic kidney cells reduces the intracellular rate of accumulation of FPPS but does not inhibit or inactivate FPPS. The endoplasmic reticulum-localizing, N-terminal amphipathic helix of viperin is specifically required for viperin to reduce cellular FPPS levels. However, although viperin reductively cleaves SAM to form 5-deoxyadenosine in a slow, uncoupled reaction characteristic of radical SAM enzymes, this cleavage reaction is independent of FPPS. Furthermore, mutation of key cysteinyl residues ligating the catalytic [Fe 4 S 4 ] cluster in the radical SAM domain, surprisingly, does not abolish the inhibitory activity of viperin against FPPS; indeed, some mutations potentiate viperin activity. These observations imply that viperin does not act as a radical SAM enzyme in regulating FPPS. Radical S-adenosyl-L-methionine-dependent (SAM)3 enzymes constitute a superfamily of enzymes that use SAM to generate free radicals (1-4). The superfamily is typified by a common CXXXCXXC motif, the cysteinyl residues of which coordinate a [Fe 4 S 4 ] cluster that is essential for radical generation. These enzymes catalyze a remarkably wide range of reactions involving an equally diverse set of substrates (2). For example, radical SAM-dependent enzymes participate in the biosynthesis of herbicides, antibiotics, vitamins, co-factors such as biotin and thiamin, and various other natural products (2, 5-8). They also function in the modification of ribosomal and transfer RNAs (9, 10) and DNA repair (11) and in the post-translational modification of peptides and proteins (12)(13)(14). Sequence analyses indicate that there are potentially thousands of members of the radical SAM superfamily, but to date, relatively few of these enzymes have been isolated and characterized (15, 16). Radical SAM enzymes were until recently thought to be confined to the microbial realm but intriguingly have now been identified in higher aerobic organisms, including plants and animals (3).Central to the mechanism of all radical SAM enzymes is the generation of a highly reactive 5Ј-deoxyadenosyl radical (Ado ⅐ ) (1,4,17). This is accomplished through one-electron reduction of SAM by the [Fe 4...

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“…95,96 An explanation for the neurodevelopmental defects in D. melanogaster could be that Elongator complex acetylate Bruchpilot, a protein important for neuronal differentiation. 97 Both in mice and C. elegans, the Elp3p homolog has been implicated in acetylating lysine 40 (K40) in a-tubulin. 98,99 However, the C. elegans elpc-3 mutant did not have a defect in a-tubulin K40 acetylation.…”

Section: Elongator Complex In Multicellular Eukaryotesmentioning

confidence: 99%

Elongator, a conserved complex required for wobble uridine modifications in Eukaryotes

Karlsborn

Tükenmez

Mahmud³

et al. 2014

RNA Biology

105

104

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ELP3 Controls Active Zone Morphology by Acetylating the ELKS Family Member Bruchpilot

Cited by 95 publications

References 54 publications

MEC-17 Deficiency Leads to Reduced α-Tubulin Acetylation and Impaired Migration of Cortical Neurons

MEC-17 Deficiency Leads to Reduced α-Tubulin Acetylation and Impaired Migration of Cortical Neurons

Does Viperin Function as a Radical S-Adenosyl-l-methionine-dependent Enzyme in Regulating Farnesylpyrophosphate Synthase Expression and Activity?

Elongator, a conserved complex required for wobble uridine modifications in Eukaryotes

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