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. 2021 Jan;16(1):101-103.
doi: 10.4103/1673-5374.286959.

Resveratrol as an inductor of autophagy: is there a unique pathway of activation?

Narayana Pineda-Ramírez  1 , Penélope Aguilera  1
Affiliations
Free PMC article

Resveratrol as an inductor of autophagy: is there a unique pathway of activation?

Narayana Pineda-Ramírez et al. Neural Regen Res. 2021 Jan.
Free PMC article
No abstract available

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Conflict of interest statement

None

Figures

Figure 1
Figure 1
Pathways of autophagy regulation. Activation of autophagy involves the inhibition of the mTORC1 by deprivation of growth-promoting stimuli (growth factors, amino acids) or by AMPK (1). The ULK1 complex regulates the class III phosphatidylinositol (PtdIns) 3-kinase complex (2). Both complexes induce the formation of the phagophore (a double membrane rich in PI3P), which elongates into a vesicle (autophagosome) (3). This elongation requires the Atg12–Atg5–Atg16 complex (4) and lipidation of LC3 (LC3-II), which are inserted in the membrane of the phagophore (5). p62 recruits’ proteins, fatty droplets, and/or organelles into the autophagosome (6). Atg4 slides the LC3-II molecules that are located on the outside of the autophagosome membrane and transforming them back into their cytosolic form (7). The autophagosome fuses with the lysosome, forming an autophagolysosome (8). RSV modulates autophagy through AMPK/mTORC1 dependent and independent pathways (9, 10). AMPK phosphorylates nuclear p53, which promotes transcription (11). Dram1 regulates autophagolysosome formation (11). Sestrin1/Sestrin2 and p38MAPK inhibit mTOR (12, 13). TSC1 and TSC2 (mTOR blockers) favor the activation of the SIRT1 pathway (14). SIRT1 activates AMPK by feedback and regulates TSC1 and TSC2 (15, 16). SIRT1, in the nucleus, deacetylates FOXO1 and FOXO3, which promote the transcription of Rab7 (autophagosomes maturation) and Bnip3 (Beclin1 regulator), and deacetylates LC3 (17–20). In the cytoplasm, SIRT1 promotes the deacetylation of the Atg 5 and Atg7, favoring phagophore elongation (21–22). RSV increases autophagy through CaMKKβ (23). Additionally, RSV activates autophagy by decreasing the TLR4/NF-κB pathway that activates mTOR (24), by inhibiting PI3K/Akt, ERK, and JNK (25). Ambra1: Activating molecule in beclin 1-regulated autophagy protein 1; AMPK: adenosine-5-monophosphate-activated protein kinase; Atg: autophagy related; Atg16L1: autophagy related 16 like 1; ATP: adenosine triphosphate; Bnip3: BCL2/adenovirus E1B 19 kDa protein-interacting protein 3; Ca2+: calcium ion; CaMKKβ: Ca2+/calmodulin-dependent protein kinase kinase β; Dram1: DNA damage regulated autophagy modulator 1 gene and protein; ERK: extracellular signal-regulated kinase; FIP200: focal adhesion kinase family interacting protein of 200 kD (ULK binding); FOXO1: Forkhead box O1 gene; FOXO3: Forkhead box O3 gene; JNK: c-Jun N-terminal kinase; LC3: microtubule-associated protein 1A/1B-light chain 3; LC3-1: microtubule-associated protein 1A/1B-light chain 3 (without C-terminal); LC3-II: microtubule-associated protein 1A/1B-light chain 3 (lipidated form); MAPK: mitogen-activated protein kinases; mTORC1: mammalian target of rapamycin complex 1; PE: phosphatidylethanolamine; PI3P: phosphatidylInositol-3-phosphate; PI3K/AKT: phosphatidylinositol-3-kinase/protein kinase B; p38: p38 mitogen-activated protein kinases; p53: p53 tumor suppressor gene; P62: sequestosome 1 (SQSTM1); Rab7: Rab7 small GTPase; RagA/B: Rag GTPase heterodimer A/B; RagC/D: Rag GTPase heterodimer C/D; Ras: Ras GTPase; Rheb: Ras homolog enriched in brain; Sesn1: Sestrin gene 1; Sesn2: Sestrin gene 2; SIRT1: Sirtuin 1; TLR4/NFκB: Toll-like receptor 4/nuclear factor kappa B; TSC1: tuberous sclerosis complex protein 1; TSC2: tuberous sclerosis complex protein 2; ULK1: Unc-51 like autophagy activating kinase 1; Vps15: phosphoinositide 3-kinase regulatory subunit 4; Vps34: vacuolar protein sorting 34.
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