The TP53INP2 Protein Is Required for Autophagy in Mammalian Cells

Nowak, Jonathan A.; Archange, Cendrine; Tardivel-Lacombe, J.; Pontarotti, Pierre; Pébusque, Marie‐Josèphe; Vaccaro, María I.; Velasco, Guillermo; Dagorn, Jean–Charles; Iovanna, Juan

doi:10.1091/mbc.e08-07-0671

Cited by 112 publications

(126 citation statements)

References 41 publications

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“…Interestingly, tumor protein 53-induced nuclear protein 2 (TP53INP2) can translocate from the nucleus to the autophagosome structures and interact with LC3 and VMP1, following activation of autophagy by rapamycin or starvation. 59 It is unknown, however, whether Beclin 1 mediates interaction between TP53INP2 and LC3/VMP1.…”

Section: Other Beclin 1-binding Proteins In Autophagymentioning

confidence: 99%

The Beclin 1 network regulates autophagy and apoptosis

et al. 2011

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Beclin 1, the mammalian orthologue of yeast Atg6, has a central role in autophagy, a process of programmed cell survival, which is increased during periods of cell stress and extinguished during the cell cycle. It interacts with several cofactors (Atg14L, UVRAG, Bif-1, Rubicon, Ambra1, HMGB1, nPIST, VMP1, SLAM, IP 3 R, PINK and survivin) to regulate the lipid kinase Vps-34 protein and promote formation of Beclin 1-Vps34-Vps15 core complexes, thereby inducing autophagy. In contrast, the BH3 domain of Beclin 1 is bound to, and inhibited by Bcl-2 or Bcl-XL. This interaction can be disrupted by phosphorylation of Bcl-2 and Beclin 1, or ubiquitination of Beclin 1. Interestingly, caspase-mediated cleavage of Beclin 1 promotes crosstalk between apoptosis and autophagy. Beclin 1 dysfunction has been implicated in many disorders, including cancer and neurodegeneration. Here, we summarize new findings regarding the organization and function of the Beclin 1 network in cellular homeostasis, focusing on the cross-regulation between apoptosis and autophagy. Cell Death and Differentiation (2011) 18, 571-580; doi:10.1038/cdd.2010 published online 11 February 2011 Autophagy is an essential process that consists of selective degradation of cellular components. There are at least three different types of autophagy described and possibly more. These autophagy types include macroautophagy (hereafter referred to as autophagy), microautophagy and chaperonemediated autophagy. 1 The initial step of autophagy is the surrounding and sequestering of cytoplasmic organelles and proteins within an isolation membrane (phagophore). Potential sources for the membrane to generate the phagophore include the Golgi complex, endosomes, the endoplasmic reticulum (ER), mitochondria and the plasma membrane. 2 The nascent membranes are fused at their edges to form double-membrane vesicles, called autophagosomes. Autophagosomes undergo a stepwise maturation process, including fusion with acidified endosomal and/or lysosomal vesicles, eventually leading to the delivery of cytoplasmic contents to lysosomal components, where they fuse, then degrade and are recycled (Figure 1a). The process of mammalian autophagy is divided into six principal steps: initiation (Figure 1b It has been well demonstrated that autophagy depends on Atg5/Atg7, is associated with microtubule-associated protein light chain 3 (LC3) truncation and lipidation, and may originate directly from the ER membrane and other membrane organelles. Furthermore, recent study has identified a Atg5/Atg7-independent pathway of autophagy. 3 This pathway of autophagy was not associated with LC3 processing but appeared to involve autophagosome formation from late endosomes and the trans-Golgi. 3 Atg7-independent autophagy had been implicated in mitochondrial clearance from reticulocytes. 4 The exact molecular basis of Atg5/Atg7-independent autophagy remains to be elucidated. Interestingly, Beclin 1 is required for Atg5/Atg7-dependent and -independent autophagy. 3 However, the presence of Beclin 1-indep...

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Section: Other Beclin 1-binding Proteins In Autophagymentioning

confidence: 99%

The Beclin 1 network regulates autophagy and apoptosis

et al. 2011

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“…52 Interestingly, TP53INP2 translocates from the nucleus to autophagosomes upon induction of autophagy, where it binds to LC3 and other LC3-family members (Gate-16, GABARAP), as well as VMP1. Therefore, TP53INP2 was proposed to act as a scaffold protein to recruit other Atg proteins to the IM.…”

Section: Ulk1 Andmentioning

confidence: 99%

Vesicular trafficking and autophagosome formation

2009

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The source of the autophagosome membrane, and the formation of the autophagosome remain the most important questions for understanding autophagy. Fundamentally, the process of autophagosome formation is similar between yeast and mammalian cells and many of the proteins involved (called the autophagy-related (Atg) proteins) are known, having been first discovered in yeast. However, both in yeast and mammalian cells, the molecular details are missing to explain how the double-membrane autophagosome is formed. Important advances in our understanding of the formation process have recently been obtained, and here, we review and interpret these data in the context of well-known paradigms of membrane trafficking to develop some hypothetical models for how an autophagosome forms in mammalian cells.

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“…TP53INP2 interacts with the pre-autophagosomal membrane protein VMP1 allowing the recruitment of LC3 to the autophagosome. 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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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 TP53INP2 Protein Is Required for Autophagy in Mammalian Cells

Cited by 112 publications

References 41 publications

The Beclin 1 network regulates autophagy and apoptosis

The Beclin 1 network regulates autophagy and apoptosis

Vesicular trafficking and autophagosome formation

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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