Macroautophagy is a key pathway for the clearance of aggregate-prone cytosolic proteins. Currently, the only suitable pharmacologic strategy for up-regulating autophagy in mammalian cells is to use rapamycin, which inhibits the mammalian target of rapamycin (mTOR), a negative regulator of autophagy. Here we describe a novel mTOR-independent pathway that regulates autophagy. We show that lithium induces autophagy, and thereby, enhances the clearance of autophagy substrates, like mutant huntingtin and α-synucleins. This effect is not mediated by glycogen synthase kinase 3β inhibition. The autophagy-enhancing properties of lithium were mediated by inhibition of inositol monophosphatase and led to free inositol depletion. This, in turn, decreased myo-inositol-1,4,5-triphosphate (IP3) levels. Our data suggest that the autophagy effect is mediated at the level of (or downstream of) lowered IP3, because it was abrogated by pharmacologic treatments that increased IP3. This novel pharmacologic strategy for autophagy induction is independent of mTOR, and may help treatment of neurodegenerative diseases, like Huntington's disease, where the toxic protein is an autophagy substrate.
Lithium induces autophagy by inhibiting inositol monophosphatase
Abbreviations used in this paper: 3-MA, 3-methyladenine; 4E-BP1, eukaryotic initiation factor 4E-binding protein 1; CBZ, carbamazepine; EGFP-HDQ74, EGFP-tagged huntingtin exon 1 with 74 polyglutamine repeats; GSK-3β, glycogen synthase kinase 3β; HD, Huntington's disease; IMPase, inositol monophosphatase; IP1-2, inositol mono- and bis-phosphate; IP3, myo-inositol-1,4,5-triphosphate; LC3, microtubule-associated protein 1 light chain 3; mTOR, mammalian target of rapamycin; PD, Parkinson's disease; PEI, prolyl endopeptidase inhibitor; S6P, ribosomal S6 protein.
Sovan Sarkar, R. Andres Floto, Zdenek Berger, Sara Imarisio, Axelle Cordenier, Matthieu Pasco, Lynnette J. Cook, David C. Rubinsztein; Lithium induces autophagy by inhibiting inositol monophosphatase . J Cell Biol 26 September 2005; 170 (7): 1101–1111. doi: https://doi.org/10.1083/jcb.200504035
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