Impact of DJ-1 and Helix 8 on the Proteome and Degradome of Neuron-Like Cells
by
Ursula Kern 1,2,†, Klemens Fröhlich 1,2,3,4,†, Johanna Bedacht 2, Nico Schmidt 2, Martin L. Biniossek 2, Nicole Gensch 5, Katja Baerenfaller 6
and 1,*
and 1,*
1
Institute of Surgical Pathology, Medical Center, University of Freiburg, Breisacher Straße 115a, D-79106 Freiburg, Germany
2
Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany
3
Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
4
Spemann Graduate School of Biology and Medicine, University of Freiburg, 79104 Freiburg, Germany
5
Core Facility Signalling Factory, BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany
6
Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, and Swiss Institute of Bioinformatics (SIB), 7265 Davos, Switzerland
*
Author to whom correspondence should be addressed.
†
These authors have contributed equally to this manuscript.
Academic Editor: Gerardo Z. Lederkremer
Cells 2021, 10(2), 404; https://doi.org/10.3390/cells10020404
Received: 22 December 2020
/
Revised: 8 February 2021
/
Accepted: 10 February 2021
/
Published: 16 February 2021
DJ-1 is an abundant and ubiquitous component of cellular proteomes. DJ-1 supposedly exerts a wide variety of molecular functions, ranging from enzymatic activities as a deglycase, protease, and esterase to chaperone functions. However, a consensus perspective on its molecular function in the cellular context has not yet been reached. Structurally, the C-terminal helix 8 of DJ-1 has been proposed to constitute a propeptide whose proteolytic removal transforms a DJ-1 zymogen to an active hydrolase with potential proteolytic activity. To better understand the cell-contextual functionality of DJ-1 and the role of helix 8, we employed post-mitotically differentiated, neuron-like SH-SY5Y neuroblastoma cells with stable over-expression of full length DJ-1 or DJ-1 lacking helix 8 (ΔH8), either with a native catalytically active site (C106) or an inactive site (C106A active site mutation). Global proteome comparison of cells over-expressing DJ-1 ΔH8 with native or mutated active site cysteine indicated a strong impact on mitochondrial biology. N-terminomic profiling however did not highlight direct protease substrate candidates for DJ-1 ΔH8, but linked DJ-1 to elevated levels of activated lysosomal proteases, albeit presumably in an indirect manner. Finally, we show that DJ-1 ΔH8 loses the deglycation activity of full length DJ-1. Our study further establishes DJ-1 as deglycation enzyme. Helix 8 is essential for the deglycation activity but dispensable for the impact on lysosomal and mitochondrial biology; further illustrating the pleiotropic nature of DJ-1.
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Keywords:
PARK7; parkinson disease; neurodegenerative disease; protease; glycase; TAILS; proteomics; degradation; lysosome; cathepsin b
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MDPI and ACS Style
Kern, U.; Fröhlich, K.; Bedacht, J.; Schmidt, N.; Biniossek, M.L.; Gensch, N.; Baerenfaller, K.; Schilling, O. Impact of DJ-1 and Helix 8 on the Proteome and Degradome of Neuron-Like Cells. Cells 2021, 10, 404. https://doi.org/10.3390/cells10020404
AMA Style
Kern U, Fröhlich K, Bedacht J, Schmidt N, Biniossek ML, Gensch N, Baerenfaller K, Schilling O. Impact of DJ-1 and Helix 8 on the Proteome and Degradome of Neuron-Like Cells. Cells. 2021; 10(2):404. https://doi.org/10.3390/cells10020404
Chicago/Turabian StyleKern, Ursula, Klemens Fröhlich, Johanna Bedacht, Nico Schmidt, Martin L. Biniossek, Nicole Gensch, Katja Baerenfaller, and Oliver Schilling. 2021. "Impact of DJ-1 and Helix 8 on the Proteome and Degradome of Neuron-Like Cells" Cells 10, no. 2: 404. https://doi.org/10.3390/cells10020404
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