Highlights
- •HMGB1 was transferred from nucleus to cytoplasm after UV irradiation in keratinocyte.
- •HMGB1 Knockdown by shRNA limited UV-induced autophagy and led to apoptosis of HaCaT.
- •Autocrine HMGB1 modulated HaCaT autophagy via a RAGE/HMGB1/Erk1/2-dependent pathway.
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.
Conclusion
Autocrine HMGB1 modulated HaCaT autophagy via a RAGE/HMGB1/extracellular signal-regulated
Erk1/2-dependent pathway to protect keratinocytes from apoptosis during UV irradiation.
Keywords
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Article info
Publication history
Published online: December 14, 2016
Accepted:
December 14,
2016
Received in revised form:
November 6,
2016
Received:
July 26,
2016
Identification
Copyright
© 2016 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.
