Publication Highlights: Articles on autophagy research published by french laboratories and selected by CFATG.
Autophagy has been proposed as a cellular process contributing to pancreatic carcinogenesis, particularly in the initial stages in which the KRAS oncogene is a key element. Indeed, activation of the pathway controlled by the KRAS oncogene generates a metabolic stress, characterized by a temporary deficit in energy which must be compensated by an increase in metabolism, through activation of autophagy. Although this concept appears clear and simple, the role of autophagy in pro- or anti-tumor development is still debated in the context of pancreatic adenocarcinoma, since multiple factors appear to conditioning this process, such as activated intracellular pathways, the genomic status of transformed pancreatic cells, as well as the physiological and pathological contexts in which the process is enabled.
Remarkably, pancreatitis is an inflammatory disease that both facilitates and accelerates the transformation of pancreatic cells upon activation of the KRAS oncogene. Autophagy is also strongly induced during pancreatitis by the overexpression of VMP1. We recently developed a genetically engineered mouse model in which the VMP1 protein is induced simultaneously with the activation of the oncogene KrasG12D specifically in the pancreas, by the addition of doxycycline to a water drink. Using this sophisticated animal model we can affirm that pancreatic autophagy, induced during pancreatitis by the overexpression of VMP1, promotes the development of precancerous lesions when induced by the mutated KRAS. In addition, the treatment of these mice with chloroquine, an inhibitor of autophagic flux, reverses the effects of VMP1 in pancreatic cancer induced by the KRAS oncogene. Overall, these results bear both mechanistic and biomedical relevance for further understanding and potentially targeting pathways which are critical for initiating pancreatic carcinogenesis, particularly if associated with pancreatitis.
Cell Death Dis. 2016;7:e2295
Graphical Abstract-High Resolution
(1) Sorbonne Universités, UPMC Univ Paris 06, INSERM, Centre d’Immunologie et des Maladies Infectieuses, U1135, CNRS 8255, Paris, France.
(2) CNRS, FRE3689, Université de Montpellier, Centre d’Études d’Agents Pathogènes et Biotechnologies pour la Santé, Montpellier, France.
(3) Unité de Génomique Virale et Vaccination, Institut Pasteur, Paris, France.
(4) Department of Dermatology and Wound Healing, Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom.
(5) Sorbonne Universités, UPMC Univ Paris 06, INSERM, Centre d’Immunologie et des Maladies Infectieuses, U1135, CNRS 8255, Paris, France; Département d’Immunologie, Assistance Publique-Hôpitaux de Paris,Hôpital Pitié-Salpêtrière, Paris, France.
(6) Unité Virus et Immunité, Institut Pasteur, Paris, France.
(7) Sorbonne Universités, UPMC Univ Paris 06, INSERM, Centre d’Immunologie et des Maladies Infectieuses, U1135, CNRS 8255, Paris, France; Département d’Immunologie, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, 75013 Paris, France.
The recent discovery of antibodies that neutralize a broad range of HIV isolates renewed optimism for developing an effective vaccine against HIV-1. These broadly neutralizing antibodies are secreted by B cells that went through multiple rounds of affinity maturation, a process controlled by CD4+ T helper cells. In fact, CD4+ T helper cells play critical roles in HIV infection, including B cell maturation, the expansion of cytotoxic responses and direct inhibition of viral replication. Therefore, understanding the basis of CD4+ T cell activation is of utmost importance.
In this work, we examined the contribution of autophagy in HIV-specific CD4+ T cell activation. Autophagy has been shown to play a major role in CD4+ T cell thymic education and on the presentation of viral antigens to CD4+ T cells. It is widely assumed that CD4+ T cells recognize antigenic peptides, presented by dendritic cells (DC), derived solely from incoming viral particles or proteins. Here, we unravel that HIV-infected DC also present newly-synthesized antigens to HIV-specific CD4+ T cells. This pathway offers a distinct possibility for the immune system to activate CD4+ T cells. We show that infected DC do not utilize autophagy to process these HIV antigens. Using HIV mutants, we suggest that it does not correspond to an escape from autophagy. However, we demonstrate that, in DC, specific targeting of HIV antigens to autophagosomes, using an LC3-fusion protein, effectively enhances and broadens HIV-specific CD4+ T cell responses. In sum, multiple pathways lead to the activation of HIV-specific CD4+ T cell responses. In particular, in the context of vaccination, targeting HIV antigens to autophagosomes might help in activating potent CD4+ T cell responses.
J Immunol. 2016;197:517-32
Graphical Abstract-High Resolution
- Increased fatty acid synthesis inhibits nitrogen starvation-induced autophagy in lipid droplet-deficient yeast. Biochem Biophys Res Commun. 2016 Aug 12;477(1):33-9.Régnacq M, Voisin P, Sere YY, Wan B, Soeroso VM, Bernard M, Camougrand N, Bernard FX, Barrault C, Bergès T.
- The Cannabinoid Receptor 2 Protects Against Alcoholic Liver Disease Via a Macrophage Autophagy-Dependent Pathway. Sci Rep. 2016 Jun 27;6:28806. Denaës T, Lodder J, Chobert MN, Ruiz I, Pawlotsky JM, Lotersztajn S, Teixeira-Clerc F.
- Caloric Restriction Mimetics Enhance Anticancer Immunosurveillance. Cancer Cell. 2016 Jul 11;30(1):147-60. Pietrocola F, Pol J, Vacchelli E, Rao S, Enot DP, Baracco EE, Levesque S, Castoldi F, Jacquelot N, Yamazaki T, Senovilla L, Marino G, Aranda F, Durand S, Sica V, Chery A, Lachkar S, Sigl V, Bloy N, Buque A, Falzoni S, Ryffel B, Apetoh L, Di Virgilio F, Madeo F, Maiuri MC, Zitvogel L, Levine B, Penninger JM, Kroemer G.
- Biomarkers of immunogenic stress in metastases from melanoma patients: Correlations with the immune infiltrate. Oncoimmunology. 2016 Mar 16;5(6):e1160193. Ladoire S, Senovilla L, Enot D, Ghiringhelli F, Poirier-Colame V, Chaba K, Erdag G, Schaefer JT, Deacon DH8, Zitvogel L, Slingluff CL Jr, Kroemer G.
- Positive impact of autophagy in human breast cancer cells on local immunosurveillance Oncoimmunology. 2016 May 24;5(6):e1174801. Ladoire S, Enot D, Senovilla L, Chaix M, Zitvogel L, Kroemer G.
- Anti-hepatitis C virus potency of a new autophagy inhibitor using human liver slices model. World J Hepatol. 2016 Jul 28;8(21):902-14. Lagaye S, Brun S, Gaston J, Shen H, Stranska R, Camus C, Dubray C, Rousseau G, Massault PP, Courcambeck J, Bassisi F, Halfon P, Pol S.
- Caspase-cleaved Tau-D(421) is colocalized with the immunophilin FKBP52 in the autophagy-endolysosomal system of Alzheimer’s disease neurons. Neurobiol Aging. 2016 Oct;46:124-37. Meduri G, Guillemeau K, Dounane O, Sazdovitch V, Duyckaerts C, Chambraud B, Baulieu EE, Giustiniani J.
- Autophagy-associated dengue vesicles promote viral transmission avoiding antibody neutralization. Sci Rep. 2016 Aug 25;6:32243. Wu YW, Mettling C, Wu SR, Yu CY, Perng GC, Lin YS, Lin YL.