Abstract：Autophagy is a highly evolutionarily conserved programmed degradation process that is essential for maintaining organism health. As a fundamental cellular metabolic process, autophagy is involved in regulating biological activities such as cell stress adaptation, stem cell differentiation, immunoregulation, learning and memory. However, the dysfunction of autophagy directly leads to various diseases including immune inflammatory disorders, neurodegenerative diseases and tumorigenesis. Uncovering the regulatory mechanism of autophagy help provide effective drug targets and therapeutic interventions for autophagy-related diseases. Previous studies have shown that many transcription factors such as FOXO, p53, and TFEB strictly and specifically regulate the process of autophagy when cells are exposed to different extracellular stress, thus enhancing or suppressing related diseases progression. This review presents an overview of the molecular mechanisms of FOXO, p53 and TFEB in regulating autophagy and elucidates their regulatory roles in diseases including tumors, in order to provide scientific and reeasonable clues for further unravelling novel functions of other transcription factors in autophagy.
[1] Dikic I, Elazar Z.Mechanism and medical implications of mammalian autophagy[J]. Nat Rev Mol Cell Biol, 2018, 19(6): 349-364. [2] Tao Z, Zheng L D, Smith C, et al.Estradiol signaling mediates gender difference in visceral adiposity via autophagy[J]. Cell Death Dis, 2018, 9(3): 309. [3] Jp C, H D C, E K, et al. Autophagy and ALS: mechanistic insights and therapeutic implications[J]. Autophagy, 2022, 18(2): 254-282. [4] Aman Y, Schmauck-Medina T, Hansen M, et al.Autophagy in healthy aging and disease[J]. Nat Aging, 2021, 1(8): 634-650. [5] Xia H, Green D R, Zou W.Autophagy in tumour immunity and therapy[J]. Nat Rev Cancer, 2021, 21(5): 281-297. [6] Kitada M, Koya D.Autophagy in metabolic disease and ageing[J]. Nat Rev Endocrinol, 2021, 17(11): 647-661. [7] Lin Y, Shi Q, Yang G, et al.A small-molecule drug inhibits autophagy gene expression through the central regulator TFEB[J]. Proc Natl Acad Sci U S A, 2023, 120(7): e2213670120. [8] Yang S, Nie T, She H, et al.Regulation of TFEB nuclear localization by HSP90AA1 promotes autophagy and longevity[J]. Autophagy, 2023, 19(3): 822-838. [9] Zhang Y, Sowers J R, Ren J.Targeting autophagy in obesity: from pathophysiology to management[J]. Nat Rev Endocrinol, 2018, 14(6): 356-376. [10] Levine B, Kroemer G.Biological Functions of Autophagy Genes: A Disease Perspective[J]. Cell, 2019, 176(1-2): 11-42. [11] Wang L, Klionsky D J, Shen H M.The emerging mechanisms and functions of microautophagy[J]. Nat Rev Mol Cell Biol, 2023, 24(3): 186-203. [12] Kaur J, Debnath J.Autophagy at the crossroads of catabolism and anabolism[J]. Nat Rev Mol Cell Biol, 2015, 16(8): 461-472. [13] Feng Y, He D, Yao Z, et al.The machinery of macroautophagy[J]. Cell Res, 2014, 24(1): 24-41. [14] Guo X, Wu C, Pan Y, et al.Mechanistic insights and implications of FOXO-SNAI interplay.[J]. Bioessays, 2022, 44(9): e2200070. [15] Guo X, Ma X, Xue L.A conserved interplay between FOXO and SNAI/snail in autophagy.[J]. Autophagy, 2022, 18(11): 2759-2760. [16] Yang D, Livingston M J, Liu Z, et al.Autophagy in diabetic kidney disease: regulation, pathological role and therapeutic potential[J]. Cell Mol Life Sci, 2018, 75(4): 669-688. [17] Sakamaki J I, Ryan K M.Transcriptional regulation of autophagy and lysosomal function by bromodomain protein BRD4[J]. Autophagy, 2017, 13(11): 2006-2007. [18] Pietrocola F, Izzo V, Niso-Santano M, et al.Regulation of autophagy by stress-responsive transcription factors[J]. Semin Cancer Biol, 2013, 23(5): 310-322. [19] Tia N, Singh A K, Pandey P, et al.Role of Forkhead Box O (FOXO) transcription factor in aging and diseases[J]. Gene, 2018, 648: 97-105. [20] Guo X, Li Z, Zhu X, et al.A coherent FOXO3-SNAI2 feed-forward loop in autophagy[J]. Proc Natl Acad Sci U S A, 2022, 119(11): e2118285119. [21] Lin S J, Chiang M C, Shih H Y, et al.Spatiotemporal expression of foxo4, foxo6a, and foxo6b in the developing brain and retina are transcriptionally regulated by PI3K signaling in zebrafish[J]. Dev Genes Evol, 2017, 227(3): 219-230. [22] Orea-Soufi A, Paik J, Bragança J, et al.FOXO transcription factors as therapeutic targets in human diseases[J]. Trends Pharmacol Sci, 2022, 43(12): 1070-1084. [23] Liu H M, Cheng M Y, Xun M H, et al.Possible Mechanisms of Oxidative Stress-Induced Skin Cellular Senescence, Inflammation, and Cancer and the Therapeutic Potential of Plant Polyphenols[J]. Int J Mol Sci, 2023, 24(4): 3755. [24] Lee S, Dong H H.FoxO integration of insulin signaling with glucose and lipid metabolism[J]. J Endocrinol, 2017, 233(2): R67-R79. [25] Zhang L, Cai M, Gong Z, et al.Geminin facilitates FoxO3 deacetylation to promote breast cancer cell metastasis[J]. J Clin Invest, 2017, 127(6): 2159-2175. [26] Ioannilli L, Ciccarone F, Ciriolo M R.Adipose Tissue and FoxO1: Bridging Physiology and Mechanisms[J]. Cells, 2020, 9(4): 849. [27] Cheng Z.The FoxO-Autophagy Axis in Health and Disease[J]. Trends Endocrinol Metab, 2019, 30(9): 658-671. [28] Cai J, Li R, Xu X, et al.CK1α suppresses lung tumour growth by stabilizing PTEN and inducing autophagy[J]. Nat Cell Biol, 2018, 20(4): 465-478. [29] Zhou J, Liao W, Yang J, et al.FOXO3 induces FOXO1-dependent autophagy by activating the AKT1 signaling pathway[J]. Autophagy, 2012, 8(12): 1712-1723. [30] Zhang H, Ge S, He K, et al.FoxO1 inhibits autophagosome-lysosome fusion leading to endothelial autophagic-apoptosis in diabetes[J]. Cardiovasc Res, 2019, 115(14): 2008-2020. [31] Chen Y, Lv L, Pi H, et al.Dihydromyricetin protects against liver ischemia/reperfusion induced apoptosis via activation of FOXO3a-mediated autophagy[J]. Oncotarget, 2016, 7(47): 76508-76522. [32] Schäffner I, Minakaki G, Khan M A, et al. FoxO Function Is Essential for Maintenance of Autophagic Flux and Neuronal Morphogenesis in Adult Neurogenesis[J]. Neuron, 2018, 99(6): 1188-1203. e6. [33] Hwang I, Oh H, Santo E, et al.FOXO protects against age-progressive axonal degeneration[J]. Aging Cell, 2018, 17(1): e12701. [34] Li L, Zviti R, Ha C, et al.Forkhead box O3(FoxO3) regulates kidney tubular autophagy following urinary tract obstruction[J]. J Biol Chem, 2017, 292(33): 13774-13783. [35] Alvarez-Garcia O, Matsuzaki T, Olmer M, et al.FOXO are required for intervertebral disk homeostasis during aging and their deficiency promotes disk degeneration[J]. Aging Cell, 2018, 17(5): e12800. [36] Matsuzaki T, Alvarez-Garcia O, Mokuda S, et al. FoxO transcription factors modulate autophagy and proteoglycan 4 in cartilage homeostasis and osteoarthritis[J]. Sci Transl Med, 2018, 10(428): eaan0746. [37] Xiong X, Tao R, DePinho R A, et al. The autophagy-related gene 14(Atg14) is regulated by forkhead box O transcription factors and circadian rhythms and plays a critical role in hepatic autophagy and lipid metabolism[J]. J Biol Chem, 2012, 287(46): 39107-39114. [38] Ghosh M, Saha S, Bettke J, et al. Mutant p53 suppresses innate immune signaling to promote tumorigenesis[J]. Cancer Cell, 2021, 39(4): 494-508. e5. [39] Yang Y, Karsli-Uzunbas G, Poillet-Perez L, et al.Autophagy promotes mammalian survival by suppressing oxidative stress and p53[J]. Genes Dev, 2020, 34(9-10): 688-700. [40] White E.The role for autophagy in cancer[J]. J Clin Invest, 2015, 125(1): 42-46. [41] White E.Autophagy and p53[J]. Cold Spring Harb Perspect Med, 2016, 6(4): a026120. [42] Liu Y, Gu W.The complexity of p53-mediated metabolic regulation in tumor suppression[J]. Semin Cancer Biol, 2022, 85: 4-32. [43] Hu W, Chen S, Thorne R F, et al.TP53, TP53 Target Genes (DRAM, TIGAR), and Autophagy[J]. Adv Exp Med Biol, 2019, 1206: 127-149. [44] Suzuki N, Johmura Y, Wang T W, et al.TP53/p53-FBXO22-TFEB controls basal autophagy to govern hormesis[J]. Autophagy, 2021, 17(11): 3776-3793. [45] Lin M, Hua R, Ma J, et al.Bisphenol A promotes autophagy in ovarian granulosa cells by inducing AMPK/mTOR/ULK1 signalling pathway[J]. Environ Int, 2021, 147: 106298. [46] Kim J, Kundu M, Viollet B, et al.AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1[J]. Nat Cell Biol, 2011, 13(2): 132-141. [47] Yang H, Xie Y, Yang D, et al.Oxidative stress-induced apoptosis in granulosa cells involves JNK, p53 and Puma[J]. Oncotarget, 2017, 8(15): 25310-25322. [48] Chen R, Kang R, Tang D.The mechanism of HMGB1 secretion and release[J]. Exp Mol Med, 2022, 54(2): 91-102. [49] Seillier M, Peuget S, Gayet O, et al.TP53INP1, a tumor suppressor, interacts with LC3 and ATG8-family proteins through the LC3-interacting region (LIR) and promotes autophagy-dependent cell death[J]. Cell Death Differ, 2012, 19(9): 1525-1535. [50] Zhang F, Peng W, Zhang J, et al.P53 and Parkin co-regulate mitophagy in bone marrow mesenchymal stem cells to promote the repair of early steroid-induced osteonecrosis of the femoral head[J]. Cell Death Dis, 2020, 11(1): 42. [51] Hoshino A, Mita Y, Okawa Y, et al.Cytosolic p53 inhibits Parkin-mediated mitophagy and promotes mitochondrial dysfunction in the mouse heart[J]. Nat Commun, 2013, 4: 2308. [52] Tan A, Prasad R, Lee C, et al.Past, present, and future perspectives of transcription factor EB (TFEB): mechanisms of regulation and association with disease[J]. Cell Death Differ, 2022, 29(8): 1433-1449. [53] Perera R M, Stoykova S, Nicolay B N, et al.Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism[J]. Nature, 2015, 524(7565): 361-365. [54] Raben N, Puertollano R.TFEB and TFE3: Linking Lysosomes to Cellular Adaptation to Stress[J]. Annu Rev Cell Dev Biol, 2016, 32: 255-278. [55] Liu X, Yin M, Dong J, et al.Tubeimoside-1 induces TFEB-dependent lysosomal degradation of PD-L1 and promotes antitumor immunity by targeting mTOR[J]. Acta Pharm Sin B, 2021, 11(10): 3134-3149. [56] Silvente-Poirot S, Segala G, Poirot M C, et al.Ligand-dependent transcriptional induction of lethal autophagy: A new perspective for cancer treatment[J]. Autophagy, 2018, 14(3): 555-557. [57] Slade L, Biswas D, Ihionu F, et al.A lysosome independent role for TFEB in activating DNA repair and inhibiting apoptosis in breast cancer cells[J]. Biochem J, 2020, 477(1): 137-160. [58] Pastore N, Huynh T, Herz N J, et al.TFEB regulates murine liver cell fate during development and regeneration[J]. Nat Commun, 2020, 11(1): 2461. [59] Ikeda S, Nah J, Shirakabe A, et al.YAP plays a crucial role in the development of cardiomyopathy in lysosomal storage diseases[J]. J Clin Invest, 2021, 131(5): e143173. [60] Martina J A, Diab H I, Brady O A, et al.TFEB and TFE3 are novel components of the integrated stress response[J]. EMBO J, 2016, 35(5): 479-495. [61] Pastore N, Brady O A, Diab H I, et al.TFEB and TFE3 cooperate in the regulation of the innate immune response in activated macrophages[J]. Autophagy, 2016, 12(8): 1240-1258. [62] Nezich C L, Wang C, Fogel A I, et al.MiT/TFE transcription factors are activated during mitophagy downstream of Parkin and Atg5[J]. J Cell Biol, 2015, 210(3): 435-450. [63] Puertollano R, Ferguson S M, Brugarolas J, et al.The complex relationship between TFEB transcription factor phosphorylation and subcellular localization[J]. EMBO J, 2018, 37(11): e98804. [64] Zhang X, Chen W, Gao Q, et al.Rapamycin directly activates lysosomal mucolipin TRP channels independent of mTOR[J]. PLoS Biol, 2019, 17(5): e3000252. [65] Napolitano G, Esposito A, Choi H, et al.mTOR-dependent phosphorylation controls TFEB nuclear export[J]. Nat Commun, 2018, 9(1): 3312. [66] Medina D L, Di Paola S, Peluso I, et al.Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB[J]. Nat Cell Biol, 2015, 17(3): 288-299.
2023,Vol. 20
