Hsp70 binds reversibly to proteasome inhibitor-induced protein aggregates and evades autophagic clearance in ARPE-19 cells

Kivinen, Niko and Hyttinen, Juha M.T. and Viiri, Johanna and Paterno, Jussi and Felszheghy, Szabolcs and Kauppinen, Anu and Salminen, Antero and Kaarniranta, Kai (2014) Hsp70 binds reversibly to proteasome inhibitor-induced protein aggregates and evades autophagic clearance in ARPE-19 cells. Journal of Biochemical and Pharmacological Research. ISSN 2168-8761

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Abstract

Age-related macular degeneration (AMD) is characterized primarily by degeneration of the macular retinal pigment epithelium (RPE) that secondarily leads to cell death of photoreceptors and impaired central vision. Hallmarks of AMD are accumulation of lysosomal lipofuscin and extracellular drusen, which indicate impaired proteolysis in RPE cells. Cellular proteostasis is strongly regulated by molecular chaperones such as Hsp70 and proteasomal and autophagic clearance systems. We have recently shown that autophagy receptor SQSTM1/p62 binds irreversibly to proteasome inhibitor–induced perinuclear protein aggregates and undergoes autophagic clearance in RPE cell cultures. Revealing decreased autophagy, SQSTM1/p62 accumulates in macular area of donor AMD patient samples. In this study, we show that Hsp70 binds reversibly to proteasome inhibitor–induced perinuclear protein aggregates and does not become degraded by autophagy in ARPE-19 cells. Our observation reveals new opportunities to use a cytoprotective Hsp70 as a therapy target in the prevention of RPE cell degeneration and development of AMD.

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