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Sci. Signal., 7 September 2010
Vol. 3, Issue 138, p. ec271
[DOI: 10.1126/scisignal.3138ec271]

EDITORS' CHOICE

Cell Biology Chaperoning mTORC1 Activity

Elizabeth M. Adler

Science Signaling, AAAS, Washington, DC 20005, USA

The mammalian target of rapamycin (mTOR) complex 1 (mTORC1) links information about growth factor abundance, cellular energy status, and nutrient availability to protein synthesis. Thus, stresses like nutrient deprivation and hypoxia, which are associated with decreased mTORC1 activity, lead to decreased protein translation. Some forms of stress, however, have more complex effects on mTORC1 signaling that depend on their intensity or duration. Noting that cell stress can lead to accumulation of misfolded proteins, Qian et al explored the connection between protein quality control and mTORC1-dependent regulation of protein synthesis. Human embryonic kidney (HEK) 293 cells grown in the presence of a 10 mM concentration of the proline analog AZC showed markedly reduced β-galactosidase (β-gal) activity but only a slight decrease in its abundance, a discrepancy likely due to β-gal misfolding. However, cells grown with 1 mM AZC showed increased β-gal abundance and activity. Similarly, 10 mM AZC decreased [35S]methionine labeling (indicative of a global decrease in translation), whereas 1 mM AZC increased it. AZC also had differential effects on phosphorylation of the mTORC1 target p70 S6K1 and its substrate ribosomal protein S6; high concentrations of AZC inhibited their phosphorylation, whereas low concentrations promoted it. Manipulation of the abundance or function of molecular chaperones (proteins that ensure the proper folding of newly synthesized polypeptides) indicated that a moderate reduction of chaperone availability promoted S6K1 phosphorylation, an effect that depended on upstream signals, whereas the complete loss of their availability suppressed it. Indeed, loss of Hsp90 function prevented the mTORC1 response to insulin signaling or loss of TSC2 (a subunit of an inhibitor of mTORC1). Immunoblot analyses of cell lysates extracted with various detergents indicated that the chaperone Hsp90 interacted with isolated components of mTORC1, but not with the assembled complex, and that loss of chaperone availability led to the relocation of mTOR and other components of the mTORC1 complex into an insoluble fraction. Live cell imaging analyses revealed that heat shock decreased the mobility of fluorescently labeled mTOR, whereas nutrient withdrawal increased it; FRET analyses of labeled forms of mTOR and the mTORC1 component Raptor indicated that these manipulations had opposing effects on formation of the mTORC1 complex. S6K1 phosphorylation was increased in mice lacking CHIP (carboxyl terminus of Hsp70/Hsp90-interacting protein), a phenotype associated with accumulation of misfolded proteins. The authors thus propose that mTORC1 links protein translation with protein quality control by sensing chaperone availability: Loss of chaperone function leads to a loss of mTORC1 signaling, whereas moderately reduced chaperone availability promotes mTORC1 assembly and signaling.

S.-B. Qian, X. Zhang, J. Sun, J. R. Bennink, J. W. Yewdell, C. Patterson, mTORC1 links protein quality and quantity control by sensing chaperone availability. J. Biol. Chem. 285, 27385–27395 (2010). [Abstract] [Full Text]

Citation: E. M. Adler, Chaperoning mTORC1 Activity. Sci. Signal. 3, ec271 (2010).



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