Figure 6.

Hypothesis of the flowchart induced by AICAR + MG132 in RPE cells. (a) According to our findings, AICAR + MG132 cotreatment induces an early translocation of HuR protein from the nucleus to the cytoplasm, accompanied by an increase of its phosphorylation in threonine residues. The activated HuR protein binds to p62 mRNA and favors its translation, upregulating p62 protein. As well, HuR protein expression is increased in this condition. Both AICAR + MG132-mediated HuR shuttling and phosphorylation are prevented by Erk inhibitor, and this possibly reverberates on p62 levels. Vice versa, AMPK is involved in HuR nucleus import, and AMPK inhibition favors both HuR permanence in the cytoplasm and p62 increase. The AICAR + MG132-induced phosphorylation of HuR is affected by inhibitors of p38^MAPK, JNK, and cPKC. p38^MAPK and JNK inhibitors seem to contrast p62 increase under AICAR + MG132 cotreatment, while PKC inhibitor has no substantial effect. For further details, see the text. (b) The ideal temporal sequela of the events with the difference between the early and late effects induced by the AICAR + MG132 cotreatment, based on present results and our previous publication [18].