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Int. J. Mol. Sci. 2017, 18(5), 1089; doi:10.3390/ijms18051089

Autophagy Regulates Proteasome Inhibitor-Induced Pigmentation in Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells

1
Faculty of Medicine and Life Sciences, BioMediTech, University of Tampere, 33014 Tampere, Finland
2
Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, 70211 Kuopio, Finland
3
School of Pharmacy, University of Eastern Finland, 70211 Kuopio, Finland
4
SIBS Labs, University of Eastern Finland, 70211 Kuopio, Finland
5
Department of Ophthalmology, University of Tampere, SILK, TAUH Eye Center, Tampere University Hospital, 33014 Tampere, Finland
6
The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
7
Department of Ophthalmology, Kuopio University Hospital, 70029 Kuopio, Finland
*
Author to whom correspondence should be addressed.
Academic Editors: Claudio Bucolo and Chiara Maria Eandi
Received: 17 January 2017 / Revised: 11 May 2017 / Accepted: 12 May 2017 / Published: 19 May 2017
(This article belongs to the Special Issue Retinal Diseases: Bridging Basic and Clinical Research)
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Abstract

The impairment of autophagic and proteasomal cleansing together with changes in pigmentation has been documented in retinal pigment epithelial (RPE) cell degeneration. However, the function and co-operation of these mechanisms in melanosome-containing RPE cells is still unclear. We show that inhibition of proteasomal degradation with MG-132 or autophagy with bafilomycin A1 increased the accumulation of premelanosomes and autophagic structures in human embryonic stem cell (hESC)-derived RPE cells. Consequently, upregulation of the autophagy marker p62 (also known as sequestosome-1, SQSTM1) was confirmed in Western blot and perinuclear staining. Interestingly, cells treated with the adenosine monophosphatedependent protein kinase activator, AICAR (5-Aminoimidazole-4-carboxamide ribonucleotide), decreased the proteasome inhibitor-induced accumulation of premelanosomes, increased the amount of autophagosomes and eradicated the protein expression of p62 and LC3 (microtubule-associated protein 1A/1B-light chain 3). These results revealed that autophagic machinery is functional in hESC-RPE cells and may regulate cellular pigmentation with proteasomes. View Full-Text
Keywords: autophagy; macula; melanosome; proteasome; stem cell autophagy; macula; melanosome; proteasome; stem cell
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Juuti-Uusitalo, K.; Koskela, A.; Kivinen, N.; Viiri, J.; Hyttinen, J.M.T.; Reinisalo, M.; Koistinen, A.; Uusitalo, H.; Sinha, D.; Skottman, H.; Kaarniranta, K. Autophagy Regulates Proteasome Inhibitor-Induced Pigmentation in Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells. Int. J. Mol. Sci. 2017, 18, 1089.

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