Autophagy in UV Damage Response

Abstract

UV radiation exposure from sunlight and artificial tanning beds is the major risk factor for the development of skin cancer and skin photoaging. UV-induced skin damage can trigger a cascade of DNA damage response signaling pathways, including cell cycle arrest, DNA repair and, if damage is irreparable, apoptosis. Compensatory proliferation replaces the apoptotic cells to maintain skin barrier integrity. Disruption of these processes can be exploited to promote carcinogenesis by allowing the survival and proliferation of damaged cells. UV radiation also induces autophagy, a catabolic process that clears unwanted or damaged proteins, lipids and organelles. The mechanisms by which autophagy is activated following UV exposure, and the functions of autophagy in UV response, are only now being clarified. Here, we summarize the current understanding of the mechanisms governing autophagy regulation by UV, the roles of autophagy in regulating cellular response to UV-induced photodamage and the implications of autophagy modulation in the treatment and prevention of photoaging and skin cancer.

Figure 1. Mechanisms of Autophagy

Autophagy is initiated upon activation of the AMPK signaling pathway. AMPK can be activated by p53 and Sesn2 in response to cellular stress. AMPK then activates TSC1/2 to inhibit mTORC1. mTORC1 is further negatively regulated by PTEN to activate autophagy. ULK1 is activated by inhibition of mTORC1, direct phosphorylation by AMPK, or p53-mediated transcriptional upregulation. ULK1 then forms a complex which activates Beclin1. Beclin1, which binds to Bcl-2 in normal conditions, dissociates from Bcl-2 and binds to UVRAG. UVRAG, a p53 target gene, promotes the formation of the Beclin1 complex to initiate phagophore nucleation. Two ubiquitin-like conjugation systems facilitate the lipidation of LC3-I to form LC3-II, and elongation of the burgeoning phagophore. E1-like activating enzyme Atg7 leads to the activation of E2-like enzyme Atg3 (System 1) or Atg10 (System 2), subsequently the activation of the E3-link enzyme complex Atg5-Atg12 conjugate with Atg16, and subsequently the generation of LC3-II. LC3-II binds to an adaptor protein or autophagy receptor, such as p62, which in turn binds to cargo with modifications such as polyubiquitination. The autophagosome encloses the cargo and subsequently fuses with a lysosome to form an autolysosome. Adaptor and cargo are degraded at the autolysosome and the resulting molecules are recycled to the cytoplasm.

Figure 2. Autophagy in UVB response

UVB radiation causes direct DNA damage in the form of photoproducts, and autophagy is induced by UVB to promote photoproduct repair. UVB directly induces autophagy activators AMPK, UVRAG and p53. p53, upon stabilization by UVB, activates transcription of AMPK, Sesn2, TSC2, and UVRAG to activate autophagy. ATR is also induced by UVB-induced DNA damage and can activate AMPK signaling. Sesn2 interacts with AMPK, TSC1, and TSC2 to activate autophagy in response to genotoxic stress. Activation of autophagy by these factors leads to the degradation of p62 and thus the decrease in Twist1 stability, which is required for XPC upregulation following UVB, and recruitment of DDB2 to sites of UVB-induced DNA damage. Conversely, autophagy activator PTEN is inhibited in response to UVB and this impairs NER by downregulating XPC.

Figure 3. Autophagy in UVA response

UVA-induced ROS production stimulates autophagy, and autophagy regulates the oxidative stress response following UVA. UVA stabilizes p53, which induces transcription of autophagy activators AMPK and Sesn2. Conversely, UVA suppresses PTEN expression, which may negatively impact autophagy induction following UVA. Autophagy clears oxidized proteins and lipids following UVA exposure, but suppresses Nrf2-mediated antioxidant response following UVA.