Autophagy: Multiple Mechanisms to Protect Skin from Ultraviolet Radiation-Driven Photoaging

Figure 3

UV radiation modulates the autophagy process via multiple signaling pathways (AMPK, PI3K/Akt, p53, and sirtuin-1). Solar UV irradiation promotes PI3K/Akt activation to inhibit TSC1/2. These signals converge on mTORC1 (mTOR, RAPTOR, and mLST8), which coordinately modifies the ULK complex to affect early steps of the autophagosome process. UV exposure also affects the signaling pathways through the mTOR-AMPK axis by activating ULK1/2 and promoting preautophagosomal structure formation. The nascent phagosome is subsequently modified by a complex of Beclin-1, ATG14, and Vps34, to form the isolation membrane structures. The expansion of the latter complex is associated with two ubiquitin-like reactions involving Atg7, Atg5, Atg12, Atg16, and Atg3 and ultimately conjugates phosphatidylethanolamine (PE) to LC3. UV activates signaling through the AMPK-Beclin-1/Vps34 complex or the p53-UVRAG-Beclin-1/Vps34 complex, which are involved in the formation of nascent phagosomes. The deacetylase sirtuin-1, a posttranscriptionally acetylating core autophagy protein, is modulated by UV to regulate LC3-I to conjugate LC3 to activate autophagy, and Atgs are involved in the conjugation machinery. LC3-PE conjugation targets LC3 to autophagosomal membranes where it is required for membrane expansion and cargo sequestration. Finally, the autophagosome is sealed and the sequestered cargo is delivered to the lysosome through autophagosome-lysosome fusion. PI3K/Akt: phosphatidylinositol 3-kinase/protein kinase B; MAPK: mitogen-activated protein kinase; mTOR: mammalian target of rapamycin; p53: tumor protein p53: sirtuin-1: silent mating type information regulation 2 homolog; PE: phosphatidylethanolamine; ULK: Unc-51-like autophagy-inhibiting kinase; UVRAG: UV resistance-associated gene; TSC: tuberous sclerosis complex; LC3: microtubule-associated protein 1A/1B light chain 3; FIP200: 200 kDa family-interacting protein.