Atg8‐family interacting motif crucial for selective autophagy

Noda, Nobuo N.; Ohsumi, Yoshinori; Inagaki, Fuyuhiko

doi:10.1016/j.febslet.2010.01.018

Cited by 494 publications

(505 citation statements)

References 56 publications

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“…It acts as a selective autophagy receptor by interacting with both ubiquitin conjugated to the target proteins and the ATG8 proteins present on the autophagosome. 14,19,57 As shown in Figure 2B, p62 comprises a N-terminal region that includes PB1 domain (residues 20-102) and zinc finger (ZZ, residues 122-167), a central region containing LIR (LC3-interacting; residues 337-343) and KIR (Keap 1-interacting; residues 346-359), and C-terminal region encompassing a ubiquitin-associated domain (UBA, residues 391-436). 21 A nuclear Table S2).…”

Section: Resultsmentioning

confidence: 99%

“…In addition, interaction of the conserved surface of ATG8 with a conserved hydrophobic W/YXXL/I motif (referred as LIR region) in cargo receptors is necessary for the selective cargo recruitment to the autophagosomes. 14,15 In mammals, at least two proteins, p62/SQSTM1/Sequestosome-1 and NBR1 (neighbor of BRCA1 gene 1), can function as cargo receptors (or cargo binding proteins) in autophagic clearance of protein aggregates. [16][17][18][19] The published data are mostly available for human p62, which itself is degraded by autophagy.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Identification and functional analysis of Joka2, a tobacco member of the family of selective autophagy cargo receptors

Zientara‐Rytter

Łukomska²,

Moniuszko³

et al. 2011

Autophagy

129

142

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Identification and functional analysis of Joka2, a tobacco member of the family of selective autophagy cargo receptors

Zientara‐Rytter

Łukomska²,

Moniuszko³

et al. 2011

Autophagy

129

142

View full text Add to dashboard Cite

“…3C, insert). This comparison revealed that the interaction of the GABARAPL2 and LC3B proteins with UBA5 LIR/UFIM is similar to the canonical LIR-dependent interaction and involves the two hydrophobic pockets HP1 and HP2 and ␤-strand 2 of the UBL as elements of the intermolecular ␤-sheet described previously (18,35). The most perturbed resonances are localized within the corresponding area of HP1 (␣-helix 2 and ␤-strand 2) and HP2 (␣-helix 3 and ␤-strand 2).…”

Section: Uba5 Interacts With Ufm1 and Lc3/gabarap Proteins Via An Evomentioning

confidence: 99%

Structural and Functional Analysis of a Novel Interaction Motif within UFM1-activating Enzyme 5 (UBA5) Required for Binding to Ubiquitin-like Proteins and Ufmylation

Habisov

Huber

Ichimura

et al. 2016

Journal of Biological Chemistry

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The covalent conjugation of ubiquitin-fold modifier 1 (UFM1) to proteins generates a signal that regulates transcription, response to cell stress, and differentiation. Ufmylation is initiated by ubiquitin-like modifier activating enzyme 5 (UBA5), which activates and transfers UFM1 to ubiquitin-fold modifierconjugating enzyme 1 (UFC1). The details of the interaction between UFM1 and UBA5 required for UFM1 activation and its downstream transfer are however unclear. In this study, we described and characterized a combined linear LC3-interacting region/UFM1-interacting motif (LIR/UFIM) within the C terminus of UBA5. This single motif ensures that UBA5 binds both UFM1 and light chain 3/␥-aminobutyric acid receptor-associated proteins (LC3/GABARAP), two ubiquitin (Ub)-like proteins. We demonstrated that LIR/UFIM is required for the full biological activity of UBA5 and for the effective transfer of UFM1 onto UFC1 and a downstream protein substrate both in vitro and in cells. Taken together, our study provides important structural and functional insights into the interaction between UBA5 and Ub-like modifiers, improving the understanding of the biology of the ufmylation pathway.

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“…25 This consensus holds an aromatic (W/F) and hydrophobic (L/I) residue content required for binding the two hydrophobic pockets present on proteins of the ATG8 family ( Figure 4b). 26,27 We hypothesized that interaction between TP53INP1 and LC3 could take place via this LIR motif. To check this hypothesis, we mutated three essential amino acids in the TP53INP1a and b LIR consensus to alanine (amino acids in red, Figure 4b).…”

Section: Tp53inp1 Is Implicated In Autophagymentioning

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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Atg8‐family interacting motif crucial for selective autophagy

Cited by 494 publications

References 56 publications

Identification and functional analysis of Joka2, a tobacco member of the family of selective autophagy cargo receptors

Identification and functional analysis of Joka2, a tobacco member of the family of selective autophagy cargo receptors

Structural and Functional Analysis of a Novel Interaction Motif within UFM1-activating Enzyme 5 (UBA5) Required for Binding to Ubiquitin-like Proteins and Ufmylation

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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