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When glucose is low, aldolase senses low fructose-1,6-bisphosphate level and promotes the translocation of AXIN\u2212liver kinase B1 (LKB1) to the lysosomal surface, which leads to the activation of AMP-activated protein kinase (AMPK) and the inhibition of RAGs, sundering mTORC1 from the lysosome and causing its inactivation. AMPK can also inactivate mTORC1 by phosphorylating Raptor and TSC2. However, the hierarchy of AXIN- and AMPK-mediated inhibition of mTORC1 remains poorly defined. Here, we show that AXIN translocation does not require AMPK expression or activity. In glucose starvation conditions, knockout of AXIN extended the half-life of mTORC1 inhibition from 15 to 60 min, whereas knockout of AMPK only extended it to 30 min. RAGBGTP (constitutively active RAGB) almost entirely blocked the lysosomal dissociation and inhibition of mTORC1 under glucose starvation, but it did not inhibit AMPK, indicating that under these conditions, it is AXIN lysosomal translocation that inhibits mTORC1, and it does so via inhibition of RAGs. 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a mimetic of AMP, which activates both cytosolic AMPK and lysosomal AMPK, fully inhibited mTORC1 even when it is stably anchored to the lysosome by RAGBGTP, whereas glucose starvation mildly inhibited such anchored mTORC1. Together, we demonstrate that the lysosomal translocation of AXIN plays a primary role in glucose starvation-triggered inhibition of mTORC1 by inhibiting RAGs, and that AMPK activity inhibits mTORC1 through phosphorylating Raptor and TSC2, especially under severe stress.<\/jats:p>","DOI":"10.1093\/lifemeta\/load005","type":"journal-article","created":{"date-parts":[[2023,3,1]],"date-time":"2023-03-01T19:53:30Z","timestamp":1677700410000},"source":"Crossref","is-referenced-by-count":25,"title":["Hierarchical inhibition of mTORC1 by glucose starvation-triggered AXIN lysosomal translocation and by AMPK"],"prefix":"10.1093","volume":"2","author":[{"given":"Mengqi","family":"Li","sequence":"first","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University , Xiamen, Fujian 361102 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Wei","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University , Xiamen, Fujian 361102 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinye","family":"Xiong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University , Xiamen, Fujian 361102 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Wei","family":"Feng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University , Xiamen, Fujian 361102 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen-Song","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University , Xiamen, Fujian 361102 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng-Cai","family":"Lin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University , Xiamen, Fujian 361102 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,3,1]]},"reference":[{"key":"2023052715423715300_CIT0001","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.cmet.2020.01.015","article-title":"AMPK and TOR: the Yin and Yang of cellular nutrient sensing and growth 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