Christian de Duve first coined the expression “autophagy” during his seminal work on the discovery of lysosomes, which led to him being awarded the Nobel Prize in Physiology or Medicine in 1974. The term was adopted to distinguish degradation of intracellular components from the uptake and degradation of extracellular substances that he called “heterophagy”. Studies until the 1990s were largely observational/morphological-based until in 1993 Yoshinori Oshumi described a genetic screen in yeast undergoing nitrogen deprivation that led to the isolation of autophagy-defective mutants now better known as ATG (AuTophaGy-related) genes. The screen identified mutants that fell into 15 complementation groups implying that at least 15 genes were involved in the regulation of autophagy in yeast undergoing nutrient deprivation, but today, 41 yeast ATG genes have been described and many (though not all) have orthologues in humans. Attempts to identify the genetic basis of autophagy led to an explosion in its research and it's not surprising that in 2016 Yoshinori Oshumi was awarded the Nobel Prize in Physiology or Medicine. Our aim here is not to exhaustively review the ever-expanding autophagy literature (>60 papers per week), but to celebrate Yoshinori Oshumi's Nobel Prize by highlighting just a few aspects that are not normally extensively covered. In an accompanying mini-review we address the role of autophagy in early-diverging eukaryote parasites that like yeast, lack lysosomes and so use a digestive vacuole to degrade autophagosome cargo and also discuss how parasitized host cells react to infection by subverting regulation of autophagy.

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GILZ (glucocorticoid-induced leucine zipper) is an ubiquitous protein whose expression is induced by glucocorticoids in lymphoid cells. We previously showed that GILZ expression is rapidly induced upon interleukin 2 deprivation in T-cells, protecting cells from apoptosis induced by forkhead box subgroup O3 (FOXO3). The aim of this work is to elucidate the molecular mechanism of FOXO factor inhibition by GILZ. We show in the myeloid cell line HL-60 and the lymphoid CTLL-2 T-cell line that GILZ down-regulates the expression of p27 KIP1 and Bim, two FOXO targets involved in cell cycle regulation and apoptosis, respectively. GILZ inhibits FOXO1, FOXO3, and FOXO4 transcriptional activities measured with natural or synthetic FOXO-responsive promoters in HL-60 cells. This inhibitory effect is independent of protein kinase B and IB kinase phosphorylation sites. GILZ does not hinder FOXO3 DNA-binding activity and does not physically interact with FOXO3. However, using fluorescence microscopy, we observe that GILZ expression provokes a Crm-1-dependent nuclear exclusion of FOXO3 leading to its relocalization to the cytoplasm. Moreover, GILZ exclusive cytoplasmic localization is a prerequisite for FOXO3 inhibition and relocalization. We propose that GILZ is a general inhibitor of FOXO factors acting through an original mechanism by preventing them from reaching target genes within the nucleus.Forkhead box subgroup O1 (FOXO1 or FKHR), FOXO3a (FKHRL1), FOXO4 (AFX), and FOXO6 constitute the mammalian FOXO family of transcription factors and achieve important functions in the regulation of genes involved in cell cycle regulation, apoptosis, DNA repair, stress response, energy metabolism, and control of lifespan (for review, see Ref. 1). These highly related members are ubiquitously expressed in all mammalian tissues, interact with the same core consensus DNA sequence, and display overlapping patterns of transcriptional activities (2). Interest about FOXO factors in the hematopoietic system is increasing due to their role in regulation of immune responses. In vitro, FOXO3 has been shown to participate in cytokine withdrawal-induced apoptosis of lymphocytes through up-regulation of Bim (3) or Puma (4). Moreover, the Fas Ligand gene has been described as a downstream target of FOXO3 in Jurkat T-lymphocytes (5). Pink1 was recently described as an anti-apoptotic FOXO3 target gene whose induction upon growth factor deprivation paradoxically prolongs lymphocyte survival (6). In vivo, FOXO3 appears to be predominant in peripheral lymphoid organs and to regulate lymphoid and myeloid homeostasis. Indeed, mice bearing a mutated FOXO3 allele presented spontaneous T-cell activation and a multisystemic inflammatory syndrome associated with lymphadenopathy (7). Moreover, adult mice with conditional deletion of FOXO1, FOXO3a, and FOXO4 showed hematopoietic stem cells with increased cell cycling and apoptosis and defective long term repopulating activity in the bone marrow (8). Somatic disruption of the three FOXO genes in mice resulted in thym...

Theileria annulata is an apicomplexan parasite that infects and transforms bovine macrophages that disseminate throughout the animal causing a leukaemia-like disease called tropical theileriosis. Using deep RNAseq of T. annulata-infected B cells and macrophages we identify a set of microRNAs induced by infection, whose expression diminishes upon loss of the hyper-disseminating phenotype of virulent transformed macrophages. We describe how infection-induced upregulation of miR-126-5p ablates JIP-2 expression to release cytosolic JNK to translocate to the nucleus and trans-activate AP-1-driven transcription of mmp9 to promote tumour dissemination. In non-disseminating attenuated macrophages miR-126-5p levels drop, JIP-2 levels increase, JNK1 is retained in the cytosol leading to decreased c-Jun phosphorylation and dampened AP-1-driven mmp9 transcription. We show that variation in miR-126-5p levels depends on the tyrosine phosphorylation status of AGO2 that is regulated by Grb2-recruitment of PTP1B. In attenuated macrophages Grb2 levels drop resulting in less PTP1B recruitment, greater AGO2 phosphorylation, less miR-126-5p associated with AGO2 and a consequent rise in JIP-2 levels. Changes in miR-126-5p levels therefore, underpin both the virulent hyper-dissemination and the attenuated dissemination of T. annulata-infected macrophages.

Apicomplexan parasites are responsible for a number of important human pathologies. Obviously, as Eukaryotes they share a number of cellular features and pathways with their respective host cells. One of them is autophagy, a process involved in the degradation of the cell's own components. These intracellular parasites nonetheless seem to present a number of original features compared to their very evolutionarily distant host cells. In mammals and other metazoans, autophagy has been identified as an important contributor to the defence against microbial pathogens. Thus, host autophagy also likely plays a key role in the control of apicomplexan parasites, although its potential manipulation and subversion by intracellular parasites creates a complex interplay in the regulation of host and parasite autophagy. In this mini-review, we summarise current knowledge on autophagy in both parasites and their host cells, in the context of infection by three Apicomplexa: Plasmodium, Toxoplasma, and Theileria.

Neglected parasitic diseases remain a major public health issue worldwide, especially in tropical and subtropical areas. Human parasite diversity is very large, ranging from protozoa to worms. In most cases, more effective and new drugs are urgently needed. Previous studies indicated that the gold(I) drug auranofin (Ridaura®) is effective against several parasites. Among new gold(I) complexes, the phosphole-containing gold(I) complex {1-phenyl-2,5-di(2-pyridyl)phosphole}AuCl (abbreviated as GoPI) is an irreversible inhibitor of both purified human glutathione and thioredoxin reductases. GoPI-sugar is a novel 1-thio-β-d-glucopyranose 2,3,4,6-tetraacetato-S-derivative that is a chimera of the structures of GoPI and auranofin, designed to improve stability and bioavailability of GoPI. These metal-ligand complexes are of particular interest because of their combined abilities to irreversibly target the essential dithiol/selenol catalytic pair of selenium-dependent thioredoxin reductase activity, and to kill cells from breast and brain tumors. In this work, screening of various parasites—protozoans, trematodes, and nematodes—was undertaken to determine the in vitro killing activity of GoPI-sugar compared to auranofin. GoPI-sugar was found to efficiently kill intramacrophagic Leishmania donovani amastigotes and adult filarial and trematode worms.

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SF-1 (NR5A1) overexpression can induce adrenocortical tumor formation in transgenic mice and is associated with more severe prognosis in patients with adrenocortical cancer. In this study we have identified Vanin-1 (Vnn1), a SF-1 target gene, as a novel modulator of the tumorigenic effect of Sf-1 overexpression in the adrenal cortex. Vanin-1 is endowed with pantetheinase activity, releasing cysteamine in tissues and regulating cell response to oxidative stress by modulating the production of glutathione. Sf-1 transgenic mice developed adrenocortical neoplastic lesions (both dysplastic and nodular) with a frequency increasing with age. Genetic ablation of the Vnn1 gene in Sf-1 transgenic mice significantly reduced the severity of neoplastic lesions in the adrenal cortex. This effect could be reversed by treatment of Sf-1 transgenic/Vnn1 null mice with cysteamine. These data show that alteration of the mechanisms controlling intracellular redox and detoxification mechanisms is relevant to the pathogenesis of adrenocortical neoplasia induced by SF-1 overexpression.