Microthermal-induced subcellular-targeted protein damage in cells on plasmonic nanosilver-modified surfaces evokes a two-phase HSP-p97/VCP response

Martin Mistrik (), Zdenek Skrott, Petr Muller, Ales Panacek, Lucie Hochvaldova, Katarina Chroma, Tereza Buchtova, Veronika Vandova, Libor Kvitek and Jiri Bartek ()
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Martin Mistrik: Palacky University
Zdenek Skrott: Palacky University
Petr Muller: Masaryk Memorial Cancer Institute
Ales Panacek: Palacky University
Lucie Hochvaldova: Palacky University
Katarina Chroma: Palacky University
Tereza Buchtova: Palacky University
Veronika Vandova: Masaryk Memorial Cancer Institute
Libor Kvitek: Palacky University
Jiri Bartek: Palacky University

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract Despite proteotoxic stress and heat shock being implicated in diverse pathologies, currently no methodology to inflict defined, subcellular thermal damage exists. Here, we present such a single-cell method compatible with laser-scanning microscopes, adopting the plasmon resonance principle. Dose-defined heat causes protein damage in subcellular compartments, rapid heat-shock chaperone recruitment, and ensuing engagement of the ubiquitin–proteasome system, providing unprecedented insights into the spatiotemporal response to thermal damage relevant for degenerative diseases, with broad applicability in biomedicine. Using this versatile method, we discover that HSP70 chaperone and its interactors are recruited to sites of thermally damaged proteins within seconds, and we report here mechanistically important determinants of such HSP70 recruitment. Finally, we demonstrate a so-far unsuspected involvement of p97(VCP) translocase in the processing of heat-damaged proteins. Overall, we report an approach to inflict targeted thermal protein damage and its application to elucidate cellular stress-response pathways that are emerging as promising therapeutic targets.

Date: 2021
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DOI: 10.1038/s41467-021-20989-9

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