Publication Highlights: March 2016-May 2016 CFATG
Publication Highlights: March 2016-May 2016
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Publication Highlights: Articles on autophagy research published by french laboratories and selected by CFATG.

The primary cilium is a microtubule-based organelle that protrudes from the surface of many cell types. The PC plays a pivotal role during embryo development and tissue homeostasis. The PC, a microtubule-based structure present at the surface of numerous cell types, is a mechanical sensor as well as a metabolite and growth factor sensor. Recently obtained evidence indicates that there is a functional interaction between the primary cilium (PC) and macroautophagy (hereafter refred to as autophagy. In the present work we show that autophagy induced by fluid flow regulates the volume of kidney epithelial cells in vitro and in vivo. Ablation of the PC blocked the induction of autophagy and the flow-dependent regulation of cell volume. In addition, inhibition of autophagy in ciliated cells impaired flow-dependent regulation of cell volume. PC-dependent of autophagy can be triggered either by Ca2+ influx via polycystin 2 or by inhibition of mTOR. Only the inhibition of mTOR signalling was required for the flow-dependent regulation of cell volume by autophagy. The role of polycystin 2-dependent autophagy remains to be investigated. Our results demonstrate that PC senses mechanical stress and triggers autophagy. Since mechanical stresses (shear stress, compression, stretching) are involved in different tissues, we speculate that PC-mediated autophagy is important in physiological adaptation to stress to maintain tissue homeostasis.
Nat Cell Biol. 2016, 18:657-67
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(1) INSERM, U1065, Equipe Biologie et Pathologie des cellules mélanocytaire: de la pigmentation cutanée au mélanome, Centre Méditerranéen de Médecine Moléculaire (C3M), Bâtiment ARCHIMED, 151 route de Saint Antoine de Ginestière, 06204 Nice cedex 3, France
(2) UFR de Médecine, Université de Nice Sophia Antipolis, 06000 Nice, France
(3) Institut de Chimie de Nice UMR UNS-CNRS 7272, Université Nice Sophia Antipolis, Parc Valrose, 06108 Nice cedex 2, France
(4) Service de Dermatologie, Hôpital Archet II, CHU, 06204 Nice, France
(5) Institute of Research on Cancer and Ageing of Nice (IRCAN), INSERM U1081, CNRS UMR7284, Nice 06107, France
(6) Laboratoire de pathologie clinique et expérimentale et Hospital-related biobank (BB-0033-00025), Hôpital Pasteur, 06002 Nice, France
(7) CNRS UMR 7275, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), 06560 Sophia Antipolis, France
(8) University Lille, CNRS, Institut Pasteur de Lille, UMR 8199 – EGID, 59000 Lille, France
(9) Equipe Biophotonique Cellulaire Fonctionnelle, Laboratoire de Physique des Lasers, Atomes et Molécules (PhLAM) GDR 2588, 59658 Villeneuve d’Ascq, France
(10) Department of Dermatology, Cancer Campus, Gustave Roussy Institute, 114, rue Edouard-Vaillant, 94805 Villejuif, France
(11) Institute for Integrative Biology of the Cell (I2BC), CNRS CEA University Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette 91198, France
(12) INSERM, U1065, Team 8, Centre Méditerranéen de Médecine Moléculaire (C3M), 151 route de Saint Antoine de Ginestière, 06204 Nice cedex 3, France
(13) Department of Life Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, UK

The melanoma, a malignant tumor developed from melanocytes is one of the most lethal cancers among young adults. Melanoma has a high capability of invasion and rapid metastasis to other organs (lymph node, lung, liver, brain…). The prognosis of metastatic melanoma is extremely pejorative, as the various protocols of chemotherapy or immunotherapy have not shown real survival benefit. Even if recently encouraging results were obtained with the PLX 4032 (Vemurafenib), an inhibitor of BRAF, these responses remain transitory. Regrettably, after a short period of remission, the melanoma acquires in all the cases, a drug resistance and the metastases develop again increasing about 6 months the life expectancy of the patient. Another therapies (anti-CTLA4 or anti PD1) which reactivates the immunity response of the patient, were recently developed. However, these therapies give an objective response in only 15 to 20 % of patients. Thus, it appears necessary to develop new drug candidates for specific biotherapy treatment of melanoma. Using structure/activity relationship studies, we developed and selected candidates (Thiazole Benzensulfonamides) exhibiting a strong death-promoting effects in melanoma cells with HA15 as the lead compound of this series. Interestingly, HA15 is active molecule on all melanoma cells independently of mutational status and on melanoma cells freshly isolated from patients sensitive or resistant to BRAF inhibitors. HA15 exhibited also a strong efficacy in xenograft mice models performed with melanoma cells sensitive and resistant to BRAF inhibitors without any sign of toxicity in mice. We next performed pan-genomic, proteomic and biochemical studies to decipher the signaling pathway, the mechanism of action and the target of the best candidates. We identified BIP, an endoplasmic reticulum protein, as the specific target of our compound. We demonstrated clearly that the interaction between our compound and BIP increases Endoplasmic Reticulum Stress and leads to melanoma cell death by concomitant induction autophagy and apoptosis mechanisms. Even though little is known about the expression and the regulation of the target in melanoma, its overexpression in various cancers is described, it is thus not surprising that this molecule was also found to be active against other liquid and solid tumors (prostate, breast, colon, pancreas, glioma, CML…). Taken together, our data suggest that our molecule has an important impact on inhibition of melanoma growth by targeting ER stress, and may therefore be developed for treatment of patients with melanoma in particular and other cancers in general.
Cancer Cell. 2016, 29:805-19
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The intestinal mucosa of Crohn disease (CD) patients is abnormally colonized with adherent-invasive Escherichia coli (AIEC). Upon AIEC infection, autophagy is induced in host cells to restrain bacterial intracellular replication. The underlying mechanism, however, remains unknown. The aim of our study was to investigate the role of the metabolic stress response EIF2AK4-EIF2A-ATF4 pathway in autophagy activation upon AIEC infection. We showed that infection of human intestinal epithelial cells with the AIEC reference strain LF82 activates the EIF2AK4-EIF2A-ATF4 pathway, inducing binding of the transcription factor ATF4 to the promoters of the autophagy genes MAP1LC3B, BECN1, SQSTM1, ATG3 and ATG7. This results in initiation of the transcription of these genes and activation of a functional autophagy. Depletion of the EIF2AK4 gene inhibits autophagy activation in response to AIEC infection, leading to increased LF82 intracellular replication and elevated pro-inflammatory cytokine production. Infection of wild-type (WT), but not eif2ak4-/- mice with the LF82 strain activates the EIF2AK4-EIF2A-ATF4 pathway, inducing autophagy gene transcription and autophagy response in enterocytes. Consequently, compared to WT mice, eif2ak4-/- mice exhibit increased intestinal colonization by LF82 bacteria and aggravated inflammation. Finally, activation of the EIF2AK4-EIF2A-ATF4 pathway was observed in the ileal biopsies from patients with noninflamed CD, but not from those with inflamed CD, suggesting that a defect in the activation of this pathway could be one of the mechanisms contributing to active CD. In conclusion, our study shows that activation of the EIF2AK4-EIF2A-ATF4 pathway upon AIEC infection serves as a host defense mechanism to induce a functional autophagy to control AIEC intracellular replication.
Autophagy. 2016, 12:770-83
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