title: HMGB1/RAGE axis promotes autophagy and protects keratinocytes from ultraviolet radiation-induced cell death.
abstract: BACKGROUND
  The primary cause of skin cancer is ultraviolet (UV) light from the sun. Keratinocytes are the predominant cell type in the epidermis and form a barrier against environmental damage, especially from UV light irradiation. Autophagy is a self-digestion mechanism for energy homeostasis at critical times during development and as a response to stress. High-mobility group protein 1 (HMGB1) is a highly conserved nuclear protein that is associated with cell autophagy.
  
  
  OBJECTIVE
  We investigated the role of HMGB1 in keratinocytes exposed to UV irradiation and its regulation of keratinocyte autophagy.
  
  
  METHODS
  Specimens of UV-exposed human skin were assayed immunohistochemically for HMGB1. HaCaT immortalized human keratinocytes were used to investigate the mechanism of HMGB1 translocation induced by UV irradiation. Levels of cytosolic reactive oxygen species (ROS) were determined by H2DCF assay, apoptosis was assayed by flow cytometry and western-blot after lentivirus-mediated shRNA targeting of HMGB1 in keratinocytes by UV irradiation. Phosphorylated-Erk1/2 expression was assayed by western blotting.
  
  
  RESULTS
  HMGB1 and its receptor (receptor for advanced glycation end products, RAGE) were both expressed by HaCaT cells, and HMGB1 was transferred from the nucleus to the cytoplasm after UV irradiation in both HaCaT and human skin keratinocytes. Knockdown of HMGB1 expression by lentivirus-mediated shRNA limited UV-induced autophagy and led to increased apoptosis of HaCaT cells. Pharmacological inhibition of HMGB1 cytoplasmic translocation by agents such as ethyl pyruvate limits starvation-induced autophagy. UV irradiation led to phosphorylation of Erk1/2 in HaCaT cells. Inhibition of RAGE and Erk1/2 limited HaCaT cell autophagy.
  
  
  CONCLUSIONS
  Autocrine HMGB1 modulated HaCaT autophagy via a RAGE/HMGB1/extracellular signal-regulated Erk1/2-dependent pathway to protect keratinocytes from apoptosis during UV irradiation.
authors.affiliation: Department of Dermatology, the Frist Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi 710061, People's Republic of China.
authors.forename: Kuanhou
authors.initials: K
authors.lastname: Mou
authors.affiliation: Department of Dermatology, the Frist Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi 710061, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Dermatology, the Frist Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi 710061, People's Republic of China.
authors.forename: Dan
authors.initials: D
authors.lastname: Han
authors.affiliation: Center for Translational Medicine, the Frist Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi 710061, People's Republic of China. Electronic address: imlipan@163.com.
authors.forename: Pan
authors.initials: P
authors.lastname: Li
mesh_terms: D017209:Apoptosis / Q000528:radiation effects; D001343:Autophagy / Q000528:radiation effects*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000502:physiology / Q000528:radiation effects*; D020935:MAP Kinase Signaling System / Q000528:radiation effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000737:chemistry / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport / Q000187:drug effects; D011773:Pyruvates / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: C000593871:AGER protein, human; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D011773:Pyruvates; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; C046522:ethyl pyruvate; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: Autophagy; HMGB1; Keratinocyte; UV irradiation