Publication Highlights: Articles on autophagy research published by french laboratories and selected by CFATG.
Mitochondria are dynamic organelles organized as a tubular network whose morphology is conditioned by constant events of fission and fusion. These processes play an essential role in maintaining normal cellular function.
In the yeast Saccharomyces cerevisiae, physical contacts between the endoplasmic reticulum (ER) and the mitochondria are established by the ERMES (ER-mitochondrial encounter structure) complex. This complex is a marker of sites for mitochondrial division, but it is also involved in a plethora of other mitochondrial functions including lipid exchange between ER and mitochondria and mitophagy.
However, it remains unclear how this complex is regulated. We show here that Mdm34 and Mdm12, two components of ERMES, are ubiquitinated by the E3 ligase Rsp5. The other ERMES components, Mdm10 and Mmm1, are not ubiquitinated under the tested conditions.
A mutation affecting the interaction of Mdm34 with Rsp5 abolishes its ubiquitination, but also the ubiquitination of Mdm12. This mutation does not change the localization of the ERMES components and does not affect the turnover of Mdm34 and Mdm12. On the other hand, this absence of ubiquitination affects the targeting of Mdm34-GFP to the vacuole (the equivalent of mammalian lysosome) under stress conditions or induction of mitophagy (nitrogen depletion). Consistent with this, the defective ubiquitination of Mdm34 leads to defects in mitophagy. We thus report here the first identification of ubiquitinated substrates participating in yeast mitophagy.
While involved in the elimination of defective organelles, autophagy also participates in the degradation of specific proteins, therefore allowing a dynamic remodeling of the cellular proteome. Recent data, demonstrating the autophagic degradation of essential proteins for chemotactic migration (paxillin, integrins), has made it possible to establish a functional link between these two processes. Nevertheless, the mode of regulation of the autophagy machinery by chemotactic receptors of the GPCR family was largely unexplored.
In this study, we demonstrate that activation of two chemotactic GPCRs, CXCR4 and UT, by their respective ligands (SDF-1 and urotensin II) induces a marked reduction in autophagosome biogenesis from their precursor structure, the phagophore. By carrying out experiments on HEK-293 and U87 cells (human glioblastoma), we demonstrate that chemotactic GPCRs exert this anti-autophagic effect by preventing the formation of pre-autophagic endosomes, a sub-population of endosomes participating in phagophore expansion. This inhibition favors the formation of the lamellipodium and its anchoring to the extracellular matrix, which are essential steps for directional migration. Finally, we found that manipulation of the autophagic status, by overexpressing the Atg5 protein, effectively inhibits the formation of cell-matrix adhesions as well as migration, two key mechanisms of tumorigenesis. This work, highlighting a functional link between GPCRs and the autophagic process, opens up innovative perspectives for the treatment of high-grade, particularly invasive glioblastomas.
- Discovery and Optimization of N-(4-(3-Aminophenyl)thiazol-2-yl)acetamide as a Novel Scaffold Active against Sensitive and Resistant Cancer Cells. J Med Chem. 2016 Sep 22;59(18):8276-92. Millet A, Plaisant M, Ronco C, Cerezo M, Abbe P, Jaune E, Cavazza E, Rocchi S, Benhida R.
- Effect of natural uranium on the UMR-106 osteoblastic cell line: impairment of the autophagic process as an underlying mechanism of uranium toxicity. Arch Toxicol. 2016 Sep 1.Pierrefite-Carle V, Santucci-Darmanin S, Breuil V, Gritsaenko T, Vidaud C, Creff G, Solari PL, Pagnotta S, Al-Sahlanee R, Auwer CD, Carle GF.
- Identification of Atg8 from Acanthamoeba castellanii by genetic complementation in Saccharomyces cerevisiae. Mol Biochem Parasitol. 2016 Nov – Dec;210(1-2):55-57.Régnacq M, Voisin P, Héchard Y, Bergès T, Braquart-Varnier C, Samba-Louaka A.
- Psammomys obesus, a unique model of metabolic syndrome, inflammation and autophagy in the pathologic development of hepatic steatosis. C R Biol. 2016 Nov – Dec;339(11-12):475-486.Sihali-Beloui O, El-Aoufi S, Maouche B, Marco S.
- Sex-specific autophagy modulation in osteoblastic lineage: a critical function to counteract bone loss in female. Oncotarget. 2016 Oct 11;7(41):66416-66428. Camuzard O, Santucci-Darmanin S, Breuil V, Cros C, Gritsaenko T, Pagnotta S, Cailleteau L, Battaglia S, Panaïa-Ferrari P, Heymann D, Carle GF, Pierrefite-Carle V.
- Mammalian target of rapamycin inhibition counterbalances the inflammatory status of immune cells in patients with chronic granulomatous disease. J Allergy Clin Immunol. 2016 Oct 1. pii: S0091-6749(16)31057-0. Gabrion A, Hmitou I, Moshous D, Neven B, Lefèvre-Utile A, Diana JS, Suarez F, Picard C, Blanche S, Fischer A, Cavazzana M, Touzot F.
- Mechanism of melanoma cells selective apoptosis induced by a photoactive NADPH analogue. Oncotarget. 2016 Dec 13;7(50):82804-82819. Rouaud F, Boucher JL, Slama-Schwok A, Rocchi S.
- Impaired CD4 T-Cell Response to Autophagy in Treated HIV-1-Infected Individuals. J Acquir Immune Defic Syndr. 2017 Feb 1;74(2):201-205. Gómez-Mora E, Robert-Hebmann V, García E, Massanella M, Clotet B, Cabrera C, Blanco J, Biard-Piechaczyk M.
- Renal Atp6ap2/(Pro)renin Receptor Is Required for Normal Vacuolar H+-ATPase Function but Not for the Renin-Angiotensin System. J Am Soc Nephrol. 2016 Nov;27(11):3320-3330. Trepiccione F, Gerber SD, Grahammer F, López-Cayuqueo KI, Baudrie V, Păunescu TG, Capen DE, Picard N, Alexander RT, Huber TB, Chambrey R, Brown D, Houillier P, Eladari D, Simons M.
- Acute accumulation of free cholesterol induces the degradation of perilipin 2 and Rab18-dependent fusion of ER and lipid droplets in cultured human hepatocytes. Mol Biol Cell. 2016 Nov 1;27(21):3293-3304. Makino A, Hullin-Matsuda F, Murate M, Abe M, Tomishige N, Fukuda M, Yamashita S, Fujimoto T, Vidal H, Lagarde M, Delton I, Kobayashi T.
- A functional endosomal pathway is necessary for lysosome biogenesis in Drosophila. BMC Cell Biol. 2016 Nov 16;17(1):36.Jacomin AC, Fauvarque MO, Taillebourg E.
- https://www.ncbi.nlm.nih.gov/pubmed/?term=27861891 J Neurochem. 2017 Feb;140(3):485-494. Moulis MF, Millet AM, Daloyau M, Miquel MC, Ronsin B, Wissinger B, Arnauné-Pelloquin L, Belenguer P.
- LC3C Contributes to Vpu-Mediated Antagonism of BST2/Tetherin Restriction on HIV-1 Release through a Non-canonical Autophagy Pathway. Cell Rep. 2016 Nov 22;17(9):2221-2233.Madjo U1, Leymarie O, Frémont S, Kuster A, Nehlich M, Gallois-Montbrun S, Janvier K, Berlioz-Torrent C.
- SIRT1 protects cardiac cells against apoptosis induced by zearalenone or its metabolites α- and β-zearalenol through an autophagy-dependent pathway. Toxicol Appl Pharmacol. 2017 Jan 1;314:82-90. Ben Salem I, Boussabbeh M, Da Silva JP, Guilbert A, Bacha H, Abid-Essefi S, Lemaire C.