Efc. Blommaart et al., PHOSPHORYLATION OF RIBOSOMAL-PROTEIN S6 IS INHIBITORY FOR AUTOPHAGY IN ISOLATED RAT HEPATOCYTES, The Journal of biological chemistry, 270(5), 1995, pp. 2320-2326
In rat hepatocytes, autophagy is known to be inhibited by amino acids,
Insulin and cell swelling promote inhibition by amino acids, Each of
the conditions leading to inhibition of autophagic proteolysis was fou
nd to be associated with phosphorylation of a 31-kDa protein that we i
dentified as ribosomal protein S6. A combination of leucine, tyrosine,
and phenylalanine, which efficiently inhibits autophagic proteolysis,
was particularly effective in stimulating S6 phosphorylation, The rel
ationship between the percentage inhibition of proteolysis and the deg
ree of Se phosphorylation was linear, Thus, inhibition of autophagy an
d phosphorylation of S6 are under the control of the same signal trans
duction pathway, Stimulation of S6 phosphorylation by the presence of
amino acids was due to activation of S6 kinase and not to inhibition o
f S6 phosphatase. The inhibition by amino acids of both autophagic pro
teolysis and autophagic sequestration of electro-injected cytosolic [C
-14]sucrose was partially prevented by rapamycin, a compound known to
inhibit activation of p70 S6 kinase, In addition, rapamycin partially
inhibited the rate of protein synthesis. We conclude that the fluxes t
hrough the autophagic and protein synthetic pathways are regulated in
an opposite manner by the degree to which S6 is phosphorylated. Possib
le mechanisms by which S6 phosphorylation can cause inhibition of auto
phagy are discussed.