Novel inhibitory action of tunicamycin homologues suggests a role for dynamic protein fatty acylation in growth cone-mediated neurite extension.

Patterson, SI

Skene, JH

United States

2016-03-01T14:33:49Z

1994-02

In neuronal growth cones, the advancing tips of elongating axons and dendrites, specific protein substrates appear to undergo cycles of posttranslational modification by covalent attachment and removal of long-chain fatty acids. We show here that ongoing fatty acylation can be inhibited selectively by long-chain homologues of the antibiotic tunicamycin, a known inhibitor of N-linked glycosylation. Tunicamycin directly inhibits transfer of palmitate to protein in a cell-free system, indicating that tunicamycin inhibition of protein palmitoylation reflects an action of the drug separate from its previously established effects on glycosylation. Tunicamycin treatment of differentiated PC12 cells or dissociated rat sensory neurons, under conditions in which protein palmitoylation is inhibited, produces a prompt cessation of neurite elongation and induces a collapse of neuronal growth cones. These growth cone responses are rapidly reversed by washout of the antibiotic, even in the absence of protein synthesis, or by addition of serum. Two additional lines of evidence suggest that the effects of tunicamycin on growth cones arise from its ability to inhibit protein long-chain acylation, rather than its previously established effects on protein glycosylation and synthesis. (a) The abilities of different tunicamycin homologues to induce growth cone collapse very systematically with the length of the fatty acyl side-chain of tunicamycin, in a manner predicted and observed for the inhibition of protein palmitoylation. Homologues with fatty acyl moieties shorter than palmitic acid (16 hydrocarbons), including potent inhibitors of glycosylation, are poor inhibitors of growth cone function. (b) The tunicamycin-induced impairment of growth cone function can be reversed by the addition of excess exogenous fatty acid, which reverses the inhibition of protein palmitoylation but has no effect on the inhibition of protein glycosylation. These results suggest an important role for dynamic protein acylation in growth cone-mediated extension of neuronal processes.

http://www.ncbi.nlm.nih.gov/pubmed/8106550

0021-9525

https://hdl.handle.net/10161/11668

eng

Rockefeller University Press

J Cell Biol

Acylation

Animals

Cells, Cultured

Fatty Acids

GAP-43 Protein

Membrane Glycoproteins

Nerve Tissue Proteins

Neurites

PC12 Cells

Palmitic Acids

Protein Processing, Post-Translational

Rats

Solubility

Tunicamycin

Novel inhibitory action of tunicamycin homologues suggests a role for dynamic protein fatty acylation in growth cone-mediated neurite extension.

Journal article

http://www.ncbi.nlm.nih.gov/pubmed/8106550

521

536

4

Basic Science Departments

Duke

Duke Institute for Brain Sciences

Duke Science & Society

Initiatives

Institutes and Provost's Academic Units

Neurobiology

School of Medicine

University Institutes and Centers

Published

124