Publication Highlights: Articles on autophagy research published by french laboratories and selected by CFATG.
The endoplasmic reticulum (ER) forms dynamic contacts with several organelles and membranes, including the plasma membrane, and these contacts are thought to have roles in lipid transport and cell signalling. Recent findings have revealed that they are involved also in organelle biogenesis, since autophagosome formation has been reported at endoplasmic reticulum (ER)-mitochondria contact sites. Here we report that autophagosome biogenesis can occur at ER-plasma membrane contacts as well, suggesting a role in autophagy regulation, by direct implication of the tethering Extended Synaptotagmins (E-Syts) proteins. Autophagy, in turn, can regulate these contacts: we show that E-Syt2 and E-Syt3 expression is affected by cell nutrients status and shear stress, both inducing an autophagy-mediated response. Imaging data revealed that early autophagic markers are recruited to E-Syts-containing domains during autophagy and that inhibition of E-Syts expression leads to a reduction in autophagosome biogenesis. E-Syts are essential for autophagy-associated PI3P synthesis at the cortical ER membrane via the recruitment of VMP1, the stabilizing ER partner of PI3KC3 complex. These results highlight the contribution of ER-plasma membrane tethers in autophagosome biogenesis regulation and herald the importance of membrane contact sites in autophagy.
Hutchinson-Gilford progeria syndrome (HGPS) is a lethal premature and accelerated aging disease caused by a de novo point mutation in LMNA encoding A-type lamins. Progerin, a truncated and toxic prelamin A issued from aberrant splicing, accumulates in HGPS cells’ nuclei and is a hallmark of the disease. Small amounts of progerin are also produced during normal aging. We show that progerin is sequestered into abnormally shaped Promyelocytic-Nuclear Bodies, identified as novel biomarkers in Progeria. We found that the proteasome inhibitor MG132 induces progerin degradation through macroautophagy and strongly reduces progerin production through downregulation of SRSF-1 and upregulation of SRSF-5, controlling prelamin A mRNA aberrant splicing. MG132 treatment improves cellular HGPS phenotypes, reduces cellular senescence and enhances viability and proliferation in HGPS fibroblasts. MG132 injection in skeletal muscle of LmnaG609G/G609G progeria mice model locally reduces SRSF-1 expression and progerin levels. Altogether, we demonstrate progerin reduction based on MG132 dual action and shed light on a promising class of molecules towards a potential therapy for children with HGPS.
- Synergistic cellular effects including mitochondrial destabilization, autophagy and apoptosis following low-level exposure to a mixture of lipophilic persistent organic pollutants. Sci Rep. 2017 Jul 5;7(1):4728. Rainey NE, Saric A, Leberre A, Dewailly E, Slomianny C, Vial G, Zeliger HI, Petit PX.
- Advanced glycation end products receptor RAGE controls myocardial dysfunction and oxidative stress in high-fat fed mice by sustaining mitochondrial dynamics and autophagy-lysosome pathway. Free Radic Biol Med. 2017 Nov;112:397-410. Yu Y, Wang L, Delguste F, Durand A, Guilbaud A, Rousselin C, Schmidt AM, Tessier F, Boulanger E, Neviere R.
- Chemotherapy treatment induces an increase of autophagy in the luminal breast cancer cell MCF7, but not in the triple-negative MDA-MB231. Sci Rep. 2017 Aug 3;7(1):7201. Garbar C, Mascaux C, Giustiniani J, Merrouche Y, Bensussan A.
- Synaptic activity protects against AD and FTD-like pathology via autophagic-lysosomal degradation.Mol Psychiatry. 2017 Jul 11. Akwa Y, Gondard E, Mann A, Capetillo-Zarate E, Alberdi E, Matute C, Marty S, Vaccari T, Lozano AM, Baulieu EE, Tampellini D.
- Dual inhibition of BDNF/TrkB and autophagy: a promising therapeutic approach for colorectal cancer J Cell Mol Med. 2017 Oct;21(10):2610-2622. Mazouffre C, Geyl S, Perraud A, Blondy S, Jauberteau MO, Mathonnet M, Verdier M.
- Distinct Contributions of Autophagy Receptors in Measles Virus Replication. Viruses. 2017 May 22;9(5). Petkova DS, Verlhac P, Rozières A, Baguet J, Claviere M, Kretz-Remy C, Mahieux R, Viret C, Faure M.
- Targeting autophagic cancer stem-cells to reverse chemoresistance in human triple negative breast cancerOncotarget. 2017 May 23;8(21):35205-35221. Bousquet G, El Bouchtaoui M, Sophie T, Leboeuf C, de Bazelaire C, Ratajczak P, Giacchetti S, de Roquancourt A, Bertheau P, Verneuil L, Feugeas JP, Espié M, Janin A.
- Autophagy controls the pathogenicity of OPA1 mutations in dominant optic atrophy J Cell Mol Med. 2017 Oct;21(10):2284-2297. Kane MS, Alban J, Desquiret-Dumas V, Gueguen N, Ishak L, Ferre M, Amati-Bonneau P, Procaccio V, Bonneau D, Lenaers G, Reynier P, Chevrollier A.
- Autophagy and TrkC/NT-3 signaling joined forces boost the hypoxic glioblastoma cell survivalCarcinogenesis. 2017 Jun 1;38(6):592-603.Jawhari S, Bessette B, Hombourger S, Durand K, Lacroix A, Labrousse F, Jauberteau MO, Ratinaud MH, Verdier M.
- Salinomycin kills cancer stem cells by sequestering iron in lysosomes.Nat Chem. 2017 Oct;9(10):1025-1033.Mai TT, Hamaï A, Hienzsch A, Cañeque T, Müller S, Wicinski J, Cabaud O, Leroy C, David A, Acevedo V, Ryo A, Ginestier C, Birnbaum D, Charafe-Jauffret E, Codogno P, Mehrpour M, Rodriguez R
- Mesenchymal stem cells sense mitochondria released from damaged cells as danger signals to activate their rescue properties.Cell Death Differ. 2017 Jul;24(7):1224-1238. Mahrouf-Yorgov M, Augeul L, Da Silva CC, Jourdan M, Rigolet M, Manin S, Ferrera R, Ovize M, Henry A, Guguin A, Meningaud JP, Dubois-Randé JL, Motterlini R, Foresti R, Rodriguez AM.