title: PI3K-mTORC1 attenuates stress response by inhibiting cap-independent Hsp70 translation.
abstract: Protein synthesis is a key regulated cellular process that links nutrient availability and organismal growth. It has long been known that some cellular proteins continue to be synthesized under conditions where global translation is severely compromised. One prominent example is the selective translation of heat shock proteins (Hsps) under stress conditions. Although the transcriptional regulation of Hsp genes has been well established, neither the specific translation-promoting features nor the regulatory mechanism of the translation machinery have been clearly defined. Here we show that the stress-induced preferential translation of Hsp70 mRNA is negatively regulated by PI3K-mTORC1 signaling. Despite the transcriptional up-regulation, the translation of Hsp70 mRNA is deficient in cells lacking tuberous sclerosis complex 2. Conversely, Hsp70 synthesis is enhanced under the reduced PI3K-mTORC1 signaling. We found that the 5' UTR of Hsp70 mRNA contributes to cap-independent translation without exhibiting typical features of internal ribosome entry site. Our findings imply a plausible mechanism for how persistent PI3K-mTORC1 signaling favors the development of age-related pathologies by attenuating stress resistance.
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Sun
authors.forename: Crystal S
authors.initials: CS
authors.lastname: Conn
authors.forename: Yan
authors.initials: Y
authors.lastname: Han
authors.forename: Vincent
authors.initials: V
authors.lastname: Yeung
authors.forename: Shu-Bing
authors.initials: SB
authors.lastname: Qian
mesh_terms: D020121:5' Untranslated Regions; D000818:Animals; D002460:Cell Line; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000502:physiology*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012315:RNA Caps / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases
chemical_list: D020121:5' Untranslated Regions; D018840:HSP70 Heat-Shock Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D011506:Proteins; D012315:RNA Caps; D058570:TOR Serine-Threonine Kinases