The nuclear cofactor DOR regulates autophagy in mammalian and <i>Drosophila</i> cells

Mauvezin, Caroline; Orpinell, Meritxell; Francis, Víctor A.; Mansilla, Francisco; Durán, Jordi; Ribas, Vicent; Palacı́n, Manuel; Boya, Patricia; Teleman, Aurelio A.; Zorzano, António

doi:10.1038/embor.2009.242

Cited by 71 publications

(113 citation statements)

References 25 publications

(34 reference statements)

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“…During and after phagophore formation, proteins are recruited to the forming autophagosome in a 'retrieve-recycle' manner. The tumor protein 53-induced nuclear protein 2 (TP53INP2; also known as and, hereafter, referred to as DOR) exits the nucleus in response to cellular stress or the activation of autophagy (Nowak et al, 2009;Mauvezin et al, 2010). Cytoplasmic DOR then localizes to autophagosomes where it interacts with the transmembrane protein VMP1 (Nowak et al, 2009).…”

Section: Lir-containing Proteins Associated With Autophagosomes and Omentioning

confidence: 99%

“…Cytoplasmic DOR then localizes to autophagosomes where it interacts with the transmembrane protein VMP1 (Nowak et al, 2009). On autophagosomes, DOR interacts with LC3B through its LIR motif (Sancho et al, 2012), but it does not colocalize with the autolysosome-associated protein LAMP1, indicating that DOR localizes only to early autophagosomes (Mauvezin et al, 2010). Through its interaction with VMP1, DOR presumably acts as a scaffold protein that recruits ATG8 proteins to the autophagosome (Nowak et al, 2009).…”

Section: Lir-containing Proteins Associated With Autophagosomes and Omentioning

confidence: 99%

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The LIR motif – crucial for selective autophagy

Birgisdottir

Lamark

Johansen

2013

Journal of Cell Science

734

492

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Summary(Macro)autophagy is a fundamental degradation process for macromolecules and organelles of vital importance for cell and tissue homeostasis. Autophagy research has gained a strong momentum in recent years because of its relevance to cancer, neurodegenerative diseases, muscular dystrophy, lipid storage disorders, development, ageing and innate immunity. Autophagy has traditionally been thought of as a bulk degradation process that is mobilized upon nutritional starvation to replenish the cell with building blocks and keep up with the energy demand. This view has recently changed dramatically following an array of papers describing various forms of selective autophagy. A main driving force has been the discovery of specific autophagy receptors that sequester cargo into forming autophagosomes (phagophores). At the heart of this selectivity lies the LC3-interacting region (LIR) motif, which ensures the targeting of autophagy receptors to LC3 (or other ATG8 family proteins) anchored in the phagophore membrane. LIR-containing proteins include cargo receptors, members of the basal autophagy apparatus, proteins associated with vesicles and of their transport, Rab GTPaseactivating proteins (GAPs) and specific signaling proteins that are degraded by selective autophagy. Here, we comment on these new insights and focus on the interactions of LIR-containing proteins with members of the ATG8 protein family.

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Section: Lir-containing Proteins Associated With Autophagosomes and Omentioning

confidence: 99%

Section: Lir-containing Proteins Associated With Autophagosomes and Omentioning

confidence: 99%

The LIR motif – crucial for selective autophagy

Birgisdottir

Lamark

Johansen

2013

Journal of Cell Science

734

492

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“…Red and green channels were split in ImageJ and the specific correlation coefficient between cytosolic red and green spots was measured using ICA Plugin (Li et al, 2004;Mauvezin et al, 2010). Pearson's correlation coefficient was quantified from those images (n>15 animals).…”

Section: Image Analysis Colocalization Analysismentioning

confidence: 99%

Coordination of autophagosome–lysosome fusion and transport by a Klp98A–Rab14 complex in Drosophila

Mauvezin

Neisch

Ayala

et al. 2016

Journal of Cell Science

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Degradation of cellular material by autophagy is essential for cell survival and homeostasis, and requires intracellular transport of autophagosomes to encounter acidic lysosomes through unknown mechanisms. Here, we identify the PX-domain-containing kinesin Klp98A as a new regulator of autophagosome formation, transport and maturation in Drosophila. Depletion of Klp98A caused abnormal clustering of autophagosomes and lysosomes at the cell center and reduced the formation of starvation-induced autophagic vesicles. Reciprocally, overexpression of Klp98A redistributed autophagic vesicles towards the cell periphery. These effects were accompanied by reduced autophagosome-lysosome fusion and autophagic degradation. In contrast, depletion of the conventional kinesin heavy chain caused a similar mislocalization of autophagosomes without perturbing their fusion with lysosomes, indicating that vesicle fusion and localization are separable and independent events. Klp98A-mediated fusion required the endolysosomal GTPase Rab14, which interacted and colocalized with Klp98A, and required Klp98A for normal localization. Thus, Klp98A coordinates the movement and fusion of autophagic vesicles by regulating their positioning and interaction with the endolysosomal compartment.

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“…11 It was also shown that TP53INP2 regulates autophagy in Drosophila cells. 12 These findings led us to hypothesize that TP53INP1 also has a role in autophagy.…”

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confidence: 99%

TP53INP1, a tumor suppressor, interacts with LC3 and ATG8-family proteins through the LC3-interacting region (LIR) and promotes autophagy-dependent cell death

et al. 2012

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TP53INP1 (tumor protein 53-induced nuclear protein 1) is a tumor suppressor, whose expression is downregulated in cancers from different organs. It was described as a p53 target gene involved in cell death, cell-cycle arrest and cellular migration. In this work, we show that TP53INP1 is also able to interact with ATG8-family proteins and to induce autophagy-dependent cell death. In agreement with this finding, we observe that TP53INP1, which is mainly nuclear, relocalizes in autophagosomes during autophagy where it is eventually degraded. TP53INP1-LC3 interaction occurs via a functional LC3-interacting region (LIR). Inactivating mutations of this sequence abolish TP53INP1-LC3 interaction, relocalize TP53INP1 in autophagosomes and decrease TP53INP1 ability to trigger cell death. Interestingly, TP53INP1 binds to ATG8-family proteins with higher affinity than p62, suggesting that it could partially displace p62 from autophagosomes, modifying thereby their composition. Moreover, silencing the expression of autophagy related genes (ATG5 or Beclin-1) or inhibiting caspase activity significantly decreases cell death induced by TP53INP1. These data indicate that cell death observed after TP53INP1-LC3 interaction depends on both autophagy and caspase activity. We conclude that TP53INP1 could act as a tumor suppressor by inducing cell death by caspasedependent autophagy. Increased resistance to cell death participates in pancreatic cancer progression. Cells unable to undergo self elimination accumulate mutations and epigenetic modifications that in turn induce uncontrolled replication. 1 Various concomitant mechanisms exist in normal cells to induce death and, as consequence, a number of known cell-death regulators are missing in cancer cells. One of the most studied is the tumor suppressor TP53, which is inactivated in 450% of pancreatic tumors. 2 p53 induces cell death by both direct permeabilization of the outer mitochondrial membrane or translocation to the nucleus where it activates the transcription of several target genes. One of the p53 target genes is TP53INP1 (tumor protein 53-induced nuclear protein 1). 3-6 p53-dependent expression of TP53INP1 is triggered in response to several stress agents such as mutagens, ethanol, heat shock or conditions promoting reactive oxygen species formation (i.e., exposure to UV light or g-irradiation). 4,6 TP53INP1 interacts with kinases, HIPK2 and PKCd, which in turn phosphorylate p53 creating a positive feedback loop between p53 and TP53INP1. 7,8 Our laboratory demonstrated that TP53INP1 is a tumor suppressor on the basis of the following observations: (i) TP53INP1 deficient mice present with an increased susceptibility to tumor development; (ii) TP53INP1 is lost at very early stages of pancreatic carcinogenesis through a mechanism involving the oncogenic miR-155 microRNA and (iii) when TP53INP1 expression is restored in pancreatic cells, it suppresses xenograft growth by increasing apoptotic cell death through a caspase-dependent mechanism. 3,9,10 More recently, in an attempt t...

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The nuclear cofactor DOR regulates autophagy in mammalian and Drosophila cells

Cited by 71 publications

References 25 publications

The LIR motif – crucial for selective autophagy

The LIR motif – crucial for selective autophagy

Coordination of autophagosome–lysosome fusion and transport by a Klp98A–Rab14 complex in Drosophila

TP53INP1, a tumor suppressor, interacts with LC3 and ATG8-family proteins through the LC3-interacting region (LIR) and promotes autophagy-dependent cell death

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