Dictyostelium Macroautophagy Mutants Vary in the Severity of Their Developmental Defects

Otto, Grant; Wu, Mary; Kazgan, Nevzat; Anderson, O. Roger; Kessin, Richard H.

doi:10.1074/jbc.m311139200

Cited by 136 publications

(177 citation statements)

References 49 publications

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“…Atg1 (Ulk1/2) is a key component of the canonical autophagy initiation complex and the Dictyostelium atg1− mutant is strictly impaired in autophagy (21). atg1− null cells were however still able to form ejectosomes closely resembling the actin-rich structures generated in wild-type cells, with the same frequency ( Fig.…”

Section: The Autophagic Machinery Is Present At the Distal Pole Of Ejmentioning

confidence: 93%

The autophagic machinery ensures nonlytic transmission of mycobacteria

Gerstenmaier

Pilla

Herrmann

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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In contrast to mechanisms mediating uptake of intracellular bacterial pathogens, bacterial egress and cell-to-cell transmission are poorly understood. Previously, we showed that the transmission of pathogenic mycobacteria between phagocytic cells also depends on nonlytic ejection through an F-actin based structure, called the ejectosome. How the host cell maintains integrity of its plasma membrane during the ejection process was unknown. Here, we reveal an unexpected function for the autophagic machinery in nonlytic spreading of bacteria. We show that ejecting mycobacteria are escorted by a distinct polar autophagocytic vacuole. If autophagy is impaired, cell-to-cell transmission is inhibited, the host plasma membrane becomes compromised and the host cells die. These findings highlight a previously unidentified, highly ordered interaction between bacteria and the autophagic pathway and might represent the ancient way to ensure nonlytic egress of bacteria.autophagy | Dictyostelium discoideum | Mycobacterium marinum | ejection

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Section: The Autophagic Machinery Is Present At the Distal Pole Of Ejmentioning

confidence: 93%

The autophagic machinery ensures nonlytic transmission of mycobacteria

Gerstenmaier

Pilla

Herrmann

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Atg1 is also a serine/threonine kinase, and its activity is enhanced under starvation in yeast (Kamada et al, 2000). The significance of Atg1 in regulating autophagy has been shown in several eukaryotes including S. cerevisiae, Dictyostelium discoideum, Drosophila melanogaster, and Caenorhabditis elegans (Meléndez et al, 2003;Otto et al, 2004;Scott et al, 2004Scott et al, , 2007. In S. cerevisiae, Atg1 null or kinase-dead mutant strains have shown defects in autophagy even under nutrient starvation or when TOR is inhibited, supporting that Atg1 plays downstream of TOR Kamada et al, 2000).…”

Section: Introductionmentioning

confidence: 95%

ULK-Atg13-FIP200 Complexes Mediate mTOR Signaling to the Autophagy Machinery

Jung

Jun

et al. 2009

MBoC

1,768

1,600

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Autophagy, the starvation-induced degradation of bulky cytosolic components, is up-regulated in mammalian cells when nutrient supplies are limited. Although mammalian target of rapamycin (mTOR) is known as the key regulator of autophagy induction, the mechanism by which mTOR regulates autophagy has remained elusive. Here, we identify that mTOR phosphorylates a mammalian homologue of Atg13 and the mammalian Atg1 homologues ULK1 and ULK2. The mammalian Atg13 binds both ULK1 and ULK2 and mediates the interaction of the ULK proteins with FIP200. The binding of Atg13 stabilizes and activates ULK and facilitates the phosphorylation of FIP200 by ULK, whereas knockdown of Atg13 inhibits autophagosome formation. Inhibition of mTOR by rapamycin or leucine deprivation, the conditions that induce autophagy, leads to dephosphorylation of ULK1, ULK2, and Atg13 and activates ULK to phosphorylate FIP200. These findings demonstrate that the ULK-Atg13-FIP200 complexes are direct targets of mTOR and important regulators of autophagy in response to mTOR signaling.

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“…Mutations in the Dictyostelium autophagy gene orthologues ATG5, ATG6, ATG7 and ATG8 have subtle effects on growth in the presence of nutrients, but survival during nitrogen starvation is severely reduced. 16,17 Loss-of-function mutations in ATG genes in plants reduce tolerance to nitrogen or carbon depletion, resulting in enhanced chlorosis, reduced seed set, accelerated leaf senescence and limited lateral root elongation. [18][19][20] Autophagy is rapidly induced during exposure of Arabidopsis seedlings to oxidative stress.…”

Section: Autophagy In Cell Survivalmentioning

confidence: 99%

Autophagy and cell death in model organisms

2008

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Autophagy evolved in unicellular eukaryotes as a means for surviving nutrient stress. During the course of evolution, as multicellular organisms developed specialized cell types and complex intracellular signalling networks, autophagy has been summoned to serve additional cellular functions. Numerous recent studies indicate that apart from its pro-survival role under nutrient limitation, autophagy also participates in cell death. However, the precise role of this catabolic process in dying cells is not fully understood. Although in certain situations autophagy has a protective function, in other types of cell death it actually contributes to cellular destruction. Simple model organisms ranging from the unicellular Saccharomyces cerevisiae to the soil amoeba Dictyostelium discoideum and the metazoans Caenorhabditis elegans and Drosophila melanogaster provide clearly defined cell death paradigms that can be used to dissect the involvement of autophagy in cell death, at the molecular level. In this review, we survey current research in simple organisms, linking autophagy to cell death and discuss the complex interplay between autophagy, cell survival and cell death. Autophagy is a self-degradation process that is essential for survival, differentiation, development, and homeostasis. There are at least three forms of autophagy -chaperonemediated autophagy, microautophagy, and macroautophagy -that differ with respect to their mechanisms, physiological functions and cargo specificity. In the best-studied form of autophagy, macroautophagy (herein referred to as autophagy), parts of the cytoplasm, long-lived proteins and intracellular organelles are sequestered within cytoplasmic double-membrane vesicles called autophagosomes or autophagic vacuoles. These characteristic vacuoles are finally delivered to lysosomes for bulk degradation (Figure 1).Autophagy was discovered in mammalian cells and has been extensively investigated in yeast. 1 These studies have identified many genes encoding proteins involved in autophagy (ATG proteins). 2 ATG proteins participate in the induction of autophagy, the formation, expansion and maturation of autophagosomes, and in the retrieval of autophagic proteins from mature autophagosomes. 3 Fusion processes occur through the t-and v-SNARE complexes, and other molecules, such as the Rab GTPases and components of the vacuolar protein-sorting (VPS) complex. Several protein kinases regulate autophagy, the best characterized being the mammalian target of rapamycin (mTOR), which negatively regulates the pathway. 4 Downstream of TOR kinase, numerous proteins encoded by ATG genes (more than 20 genes in yeast) are essential for the execution of autophagy. 5 The autophagic process is evolutionarily conserved and most yeast ATG genes have homologues in higher organisms (Table 1).Autophagy has also been linked to cell death pathways. Indeed, excess cytoplasmic vacuolation is the main feature of type II programmed cell death or autophagic cell death. Both protective and destructive contributions of autop...

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Dictyostelium Macroautophagy Mutants Vary in the Severity of Their Developmental Defects

Cited by 136 publications

References 49 publications

The autophagic machinery ensures nonlytic transmission of mycobacteria

The autophagic machinery ensures nonlytic transmission of mycobacteria

ULK-Atg13-FIP200 Complexes Mediate mTOR Signaling to the Autophagy Machinery

Autophagy and cell death in model organisms

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