Abstract
Hypoxic conditions induce the activation of hypoxia-inducible factor-1α (HIF-1α) to restore the supply of oxygen to tissues and cells. Activated HIF-1α translocates into the nucleus and binds to hypoxia response elements to promote the transcription of target genes. Cathepsin L (CTSL) is a lysosomal protease that degrades cellular proteins via the endolysosomal pathway. In this study, we attempted to determine if CTSL is a hypoxia responsive target gene of HIF-1α, and decipher its role in melanocytes in association with the autophagic pathway. The results of our luciferase reporter assay showed that the expression of CTSL is transcriptionally activated through the binding of HIF1-α at its promoter. Under autophagy-inducing starvation conditions, HIF-1α and CTSL expression is highly upregulated in melan-a cells. The mature form of CTSL is closely involved in melanosome degradation through lysosomal activity upon autophagosome–lysosome fusion. The inhibition of conversion of pro-CTSL to mature CTSL leads to the accumulation of gp100 and tyrosinase in addition to microtubule-associated protein 1 light chain 3 (LC3) II, due to decreased lysosomal activity in the autophagic pathway. In conclusion, we have identified that CTSL, a novel target of HIF-1α, participates in melanosome degradation in melanocytes through lysosomal activity during autophagosome–lysosome fusion.
Highlights
Hypoxia is a state in which tissues are deprived of oxygen supply
Luciferase assay results demonstrate that cells transfected with wild-type construct showed higher luciferase activity in hypoxia conditions compared to normoxia (Figure 1e)
The present study has demonstrated that Cathepsin L (CTSL) transcription is regulated by hypoxia-inducible factor-1α (HIF-1α) expression
Summary
Hypoxia is a state in which tissues are deprived of oxygen supply. Oxygen acts as a terminal electron acceptor in the mitochondria of cells; a low supply of oxygen is closely related to the pathology of diseases such as cancer, aging, and diabetes [1]. Cells recognize changes in oxygen concentration and respond to low oxygen concentrations by activating hypoxia-inducible factor-1 (HIF-1). Among the HIF-1 subunits, the status of HIF-1α determines the activity of HIF-1 and is known as a transcriptional regulator of the hypoxia-responsive genes that are related to cell proliferation, survival, death, cytoskeletal structure, and angiogenesis [2]. Under hypoxic or hypoxia mimicking conditions, accumulated HIF-1α is translocated to the nucleus and binds to hypoxia response elements (HRE) in the genome containing the sequence 5 -RCGTG-3 (R, purine (A or G)) to activate the transcription of target genes, including vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), and phosphoglycerate kinase 1 (PGK1) [3,4,5]. Skin has been reported to be a participant in response to hypoxia. To understand the elaborate network of HIF-1α, the mechanism of HIF-1α and its target genes needs to be investigated
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