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Communication

In Vivo Remodeling of Altered Autophagy-Lysosomal Pathway by a Phosphopeptide in Lupus

1
Biotechnology and Cell Signaling, CNRS-University of Strasbourg, Illkirch, France/Laboratory of Excellence Medalis, Institut de Science et d’Ingénierie Supramoléculaire, 67000 Strasbourg, France
2
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
3
Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY 10461, USA
4
Fédération Hospitalo-Universitaire (FHU) OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg University, 67000 Strasbourg, France
5
University of Strasbourg Institute for Advanced Study (USIAS), 67000 Strasbourg, France
*
Author to whom correspondence should be addressed.
Cells 2020, 9(10), 2328; https://doi.org/10.3390/cells9102328
Received: 23 August 2020 / Revised: 30 September 2020 / Accepted: 16 October 2020 / Published: 20 October 2020
The phosphopeptide P140/Lupuzor, which improves the course of lupus disease in mice and patients, targets chaperone-mediated autophagy (CMA), a selective form of autophagy that is abnormally upregulated in lupus-prone MRL/lpr mice. Administered intravenously to diseased mice, P140 reduces the expression level of two major protein players of CMA, LAMP2A and HSPA8, and inhibits CMA in vitro in a cell line that stably expresses a CMA reporter. Here, we aimed to demonstrate that P140 also affects CMA in vivo and to unravel the precise cellular mechanism of how P140 interacts with the CMA process. MRL/lpr mice and CBA/J mice used as control received P140 or control peptides intravenously. Lysosome-enriched fractions of spleen or liver were prepared to examine lysosomal function. Highly purified lysosomes were further isolated and left to incubate with the CMA substrate to study at which cellular step P140 interacts with the CMA process. The data show that P140 effectively regulates CMA in vivo in MRL/lpr mice at the step of substrate lysosomal uptake and restores some alterations of defective lysosomes. For the first time, it is demonstrated that by occluding the intralysosome uptake of CMA substrates, a therapeutic molecule can attenuate excessive CMA activity in a pathological pro-inflammatory context and protect against hyperinflammation. This recovery effect of P140 on hyperactivated CMA is not only important for lupus therapy but potentially also for treating other (auto)inflammatory diseases, including neurologic and metabolic disorders, where CMA modulation would be highly beneficial. View Full-Text
Keywords: chaperone-mediated autophagy; lysosomes; lupus; MRL/lpr mice; P140 peptide chaperone-mediated autophagy; lysosomes; lupus; MRL/lpr mice; P140 peptide
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MDPI and ACS Style

Wang, F.; Tasset, I.; Cuervo, A.M.; Muller, S. In Vivo Remodeling of Altered Autophagy-Lysosomal Pathway by a Phosphopeptide in Lupus. Cells 2020, 9, 2328. https://doi.org/10.3390/cells9102328

AMA Style

Wang F, Tasset I, Cuervo AM, Muller S. In Vivo Remodeling of Altered Autophagy-Lysosomal Pathway by a Phosphopeptide in Lupus. Cells. 2020; 9(10):2328. https://doi.org/10.3390/cells9102328

Chicago/Turabian Style

Wang, Fengjuan, Inmaculada Tasset, Ana Maria Cuervo, and Sylviane Muller. 2020. "In Vivo Remodeling of Altered Autophagy-Lysosomal Pathway by a Phosphopeptide in Lupus" Cells 9, no. 10: 2328. https://doi.org/10.3390/cells9102328

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