IGF-1 Receptor Antagonism Inhibits Autophagy
- Authors
- Renna, M., Figueira-Bento, C., Fleming, A., Menzies, F.M., Siddiqi, F.H., Ravikumar, B., Puri, C., Garcia-Arencibia, M., Sadiq, O., Corrochano, S., Carter, S., Brown, S.D., Acevedo-Arozena, A., and Rubinsztein, D.C.
- ID
- ZDB-PUB-130710-82
- Date
- 2013
- Source
- Human molecular genetics 22(22): 4528-44 (Journal)
- Registered Authors
- Fleming, Angeleen
- Keywords
- none
- MeSH Terms
-
- Humans
- Mice
- Cell Line
- Multiprotein Complexes/genetics
- Multiprotein Complexes/metabolism
- Signal Transduction/drug effects*
- Signal Transduction/genetics
- Enzyme Inhibitors/pharmacology
- Models, Animal
- Neurodegenerative Diseases/drug therapy
- Neurodegenerative Diseases/pathology
- Insulin-Like Growth Factor I/antagonists & inhibitors*
- Insulin-Like Growth Factor I/metabolism
- Mice, Inbred C57BL
- TOR Serine-Threonine Kinases/genetics
- TOR Serine-Threonine Kinases/metabolism
- Autophagy/drug effects*
- HeLa Cells
- Zebrafish/genetics
- Zebrafish/metabolism
- Animals
- Protein Kinase C/genetics
- Protein Kinase C/metabolism
- Macrolides/pharmacology
- Receptor, IGF Type 1/antagonists & inhibitors*
- Receptor, IGF Type 1/genetics*
- PubMed
- 23804751 Full text @ Hum. Mol. Genet.
Inhibition of the insulin/insulin-like growth factor signalling pathway increases lifespan and protects against neurodegeneration in model organisms, and has been considered as a potential therapeutic target. This pathway is upstream of mTORC1, a negative regulator of autophagy. Thus, we expected autophagy to be activated by IGF-1 inhibition, which could account for many of its beneficial effects. Paradoxically, we found that IGF-1 inhibition attenuates autophagosome formation. The reduced amount of autophagosomes present in IGF-1R depleted cells can be, at least in part, explained by a reduced formation of autophagosomal precursors at the plasma membrane. In particular, IGF-1R depletion inhibits mTORC2, which, in turn, reduces the activity of PKCα/β. This perturbs the actin cytoskeleton dynamics and decreases the rate of clathrin-dependent endocytosis, which impacts on autophagosome precursor formation.
Finally, with important implications for human diseases, we demonstrate that pharmacological inhibition of the IGF-1R signalling cascade reduces autophagy also in zebrafish and mice models. The novel link we describe here has important consequences for the interpretation of genetic experiments in mammalian systems and for evaluating the potential of targeting the IGF-1R receptor or modulating its signalling through the downstream pathway for therapeutic purposes in clinically relevant conditions, such as neurodegenerative diseases, where autophagy stimulation is considered beneficial.