INVESTIGADORES
PATTERSON Sean Ingram
artículos
Título:
Novel inhibitory action of tunicamycin homologues suggests a role for dynamic protein fatty acylation in growth cone-mediated neurite extension
Autor/es:
SEAN I. PATTERSON; J.H. PATE SKENE
Revista:
JOURNAL OF CELL BIOLOGY
Referencias:
Año: 1994 vol. 124 p. 521 - 536
ISSN:
0021-9525
Resumen:
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.