The Experts below are selected from a list of 6684 Experts worldwide ranked by ideXlab platform
Yoshinori Ohsumi - One of the best experts on this subject based on the ideXlab platform.
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Atg9 is a lipid scramblase that mediates autophagosomal membrane expansion
Nature Structural & Molecular Biology, 2020Co-Authors: Kazuaki Matoba, Daisuke Noshiro, Tetsuya Kotani, Akihisa Tsutsumi, Takuma Tsuji, Takaharu Mori, Yuji Sugita, Norimichi Nomura, So Iwata, Yoshinori OhsumiAbstract:The molecular function of Atg9, the sole transmembrane protein in the autophagosome-forming machinery, remains unknown. Atg9 colocalizes with Atg2 at the expanding edge of the isolation membrane (IM), where Atg2 receives phospholipids from the endoplasmic reticulum (ER). Here we report that yeast and human Atg9 are lipid scramblases that translocate phospholipids between outer and inner leaflets of liposomes in vitro. Cryo-EM of fission yeast Atg9 reveals a homotrimer, with two connected pores forming a path between the two membrane leaflets: one pore, located at a protomer, opens laterally to the cytoplasmic leaflet; the other, at the trimer center, traverses the membrane vertically. Mutation of residues lining the pores impaired IM expansion and autophagy activity in yeast and abolished Atg9’s ability to transport phospholipids between liposome leaflets. These results suggest that phospholipids delivered by Atg2 are translocated from the cytoplasmic to the luminal leaflet by Atg9, thereby driving autophagosomal membrane expansion. Cryo-EM and liposome assays reveal that Atg9 functions as a lipid scramblase, transporting phospholipids between inner and outer liposome leaflets. Analyses of mutants in yeast support a role for this activity in autophagy.
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Two distinct mechanisms target the autophagy-related E3 complex to the pre-autophagosomal structure.
eLife, 2019Co-Authors: Kumi Harada, Machiko Sakoh-nakatogawa, Hayashi Yamamoto, Tetsuya Kotani, Yu Oikawa, Yayoi Kimura, Hiromi Kirisako, Yoshinori Ohsumi, Hisashi Hirano, Hitoshi NakatogawaAbstract:In autophagy, Atg proteins organize the pre-autophagosomal structure (PAS) to initiate autophagosome formation. Previous studies in yeast revealed that the autophagy-related E3 complex Atg12-Atg5-Atg16 is recruited to the PAS via Atg16 interaction with Atg21, which binds phosphatidylinositol 3-phosphate (PI3P) produced at the PAS, to stimulate conjugation of the ubiquitin-like protein Atg8 to phosphatidylethanolamine. Here, we discover a novel mechanism for the PAS targeting of Atg12-Atg5-Atg16, which is mediated by the interaction of Atg12 with the Atg1 kinase complex that serves as a scaffold for PAS organization. While autophagy is partially defective without one of these mechanisms, cells lacking both completely lose the PAS localization of Atg12-Atg5-Atg16 and show no autophagic activity. As with the PI3P-dependent mechanism, Atg12-Atg5-Atg16 recruited via the Atg12-dependent mechanism stimulates Atg8 lipidation, but also has the specific function of facilitating PAS scaffold assembly. Thus, this study significantly advances our understanding of the nucleation step in autophagosome formation.
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ATG7 Activates an Autophagy-Essential Ubiquitin-like Protein Atg8 through Multi-Step Recognition.
Journal of Molecular Biology, 2018Co-Authors: Masaya Yamaguchi, Hironori Suzuki, Yuko Fujioka, Fuyuhiko Inagaki, Yoshinori Ohsumi, Kenji Satoo, Nobuo N. NodaAbstract:Atg8 is a unique ubiquitin-like protein that is covalently conjugated with a phosphatidylethanolamine through reactions similar to ubiquitination and plays essential roles in autophagy. ATG7 is the E1 enzyme for Atg8, and it activates the C-terminal Gly116 of Atg8 using ATP. Here, we report the crystal structure of Atg8 bound to the C-terminal domain of ATG7 in an unprecedented mode. Atg8 neither contacts with the central β-sheet nor binds to the catalytic site of ATG7, both of which were observed in previously reported ATG7-Atg8 structures. Instead, Atg8 binds to the C-terminal α-helix and crossover loop, thereby changing the autoinhibited conformation of the crossover loop observed in the free ATG7 structure into a short helix and a disordered loop. Mutational analyses suggested that this interaction mode is important for the activation reaction. We propose that ATG7 recognizes Atg8 through multiple steps, which would be necessary to induce a conformational change in ATG7 that is optimal for the activation reaction.
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atg12 atg5 conjugate enhances e2 activity of atg3 by rearranging its catalytic site
Nature Structural & Molecular Biology, 2013Co-Authors: Machiko Sakohnakatogawa, Eri Asai, Kazuaki Matoba, Junko Ishii, Nobuo N. Noda, Fuyuhiko Inagaki, Hiromi Kirisako, Hitoshi Nakatogawa, Yoshinori OhsumiAbstract:In the yeast autophagy system, the Atg12–Atg5 conjugate acts as an E3 to promote the E2 activity of Atg3, which conjugates Atg8 to phosphatidylethanolamine. Now structural and biochemical analyses reveal that Atg12–Atg5 induces a rearrangement in the catalytic center of Atg3, which employs a threonine residue in addition to the active cysteine to catalyze the conjugation reaction.
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Atg12–Atg5 conjugate enhances E2 activity of Atg3 by rearranging its catalytic site
Nature Structural & Molecular Biology, 2013Co-Authors: Machiko Sakoh-nakatogawa, Eri Asai, Kazuaki Matoba, Junko Ishii, Nobuo N. Noda, Fuyuhiko Inagaki, Hiromi Kirisako, Hitoshi Nakatogawa, Yoshinori OhsumiAbstract:In the yeast autophagy system, the Atg12–Atg5 conjugate acts as an E3 to promote the E2 activity of Atg3, which conjugates Atg8 to phosphatidylethanolamine. Now structural and biochemical analyses reveal that Atg12–Atg5 induces a rearrangement in the catalytic center of Atg3, which employs a threonine residue in addition to the active cysteine to catalyze the conjugation reaction.
Fuyuhiko Inagaki - One of the best experts on this subject based on the ideXlab platform.
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ATG7 Activates an Autophagy-Essential Ubiquitin-like Protein Atg8 through Multi-Step Recognition.
Journal of Molecular Biology, 2018Co-Authors: Masaya Yamaguchi, Hironori Suzuki, Yuko Fujioka, Fuyuhiko Inagaki, Yoshinori Ohsumi, Kenji Satoo, Nobuo N. NodaAbstract:Atg8 is a unique ubiquitin-like protein that is covalently conjugated with a phosphatidylethanolamine through reactions similar to ubiquitination and plays essential roles in autophagy. ATG7 is the E1 enzyme for Atg8, and it activates the C-terminal Gly116 of Atg8 using ATP. Here, we report the crystal structure of Atg8 bound to the C-terminal domain of ATG7 in an unprecedented mode. Atg8 neither contacts with the central β-sheet nor binds to the catalytic site of ATG7, both of which were observed in previously reported ATG7-Atg8 structures. Instead, Atg8 binds to the C-terminal α-helix and crossover loop, thereby changing the autoinhibited conformation of the crossover loop observed in the free ATG7 structure into a short helix and a disordered loop. Mutational analyses suggested that this interaction mode is important for the activation reaction. We propose that ATG7 recognizes Atg8 through multiple steps, which would be necessary to induce a conformational change in ATG7 that is optimal for the activation reaction.
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architecture of the atg12 atg5 atg16 complex and its molecular role in autophagy
Autophagy: Cancer Other Pathologies Inflammation Immunity Infection and Aging#R##N#Volume 3 - Mitophagy, 2014Co-Authors: Nobuo N. Noda, Fuyuhiko InagakiAbstract:Atg5 is covalently modified with Atg12 via reactions that are similar to ubiquitination, and it noncovalently interacts with Atg16. Formation of the Atg12–Atg5–Atg16 complex is essential for its E3-like function: facilitation of Atg8 transfer from Atg3 to phosphatidylethanolamine at autophagic membranes. Structural studies on the Atg12–Atg5–Atg16 complex revealed that the unique architecture of this protein complex is totally distinct from the other E3 enzymes. The Atg12–Atg5–Atg16 complex interacts directly with Atg3 via Atg12, and enhances the conjugase activity of Atg3 by rearranging its catalytic center, while it is targeted to the membranes via Atg5 and Atg16, and promotes the transfer of Atg8 from Atg3 to the membranes.
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atg12 atg5 conjugate enhances e2 activity of atg3 by rearranging its catalytic site
Nature Structural & Molecular Biology, 2013Co-Authors: Machiko Sakohnakatogawa, Eri Asai, Kazuaki Matoba, Junko Ishii, Nobuo N. Noda, Fuyuhiko Inagaki, Hiromi Kirisako, Hitoshi Nakatogawa, Yoshinori OhsumiAbstract:In the yeast autophagy system, the Atg12–Atg5 conjugate acts as an E3 to promote the E2 activity of Atg3, which conjugates Atg8 to phosphatidylethanolamine. Now structural and biochemical analyses reveal that Atg12–Atg5 induces a rearrangement in the catalytic center of Atg3, which employs a threonine residue in addition to the active cysteine to catalyze the conjugation reaction.
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Atg12–Atg5 conjugate enhances E2 activity of Atg3 by rearranging its catalytic site
Nature Structural & Molecular Biology, 2013Co-Authors: Machiko Sakoh-nakatogawa, Eri Asai, Kazuaki Matoba, Junko Ishii, Nobuo N. Noda, Fuyuhiko Inagaki, Hiromi Kirisako, Hitoshi Nakatogawa, Yoshinori OhsumiAbstract:In the yeast autophagy system, the Atg12–Atg5 conjugate acts as an E3 to promote the E2 activity of Atg3, which conjugates Atg8 to phosphatidylethanolamine. Now structural and biochemical analyses reveal that Atg12–Atg5 induces a rearrangement in the catalytic center of Atg3, which employs a threonine residue in addition to the active cysteine to catalyze the conjugation reaction.
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structure of the atg12 atg5 conjugate reveals a platform for stimulating atg8 pe conjugation
EMBO Reports, 2013Co-Authors: Nobuo N. Noda, Takao Hanada, Yuko Fujioka, Yoshinori Ohsumi, Fuyuhiko InagakiAbstract:Atg12 is conjugated to Atg5 through enzymatic reactions similar to ubiquitination. The Atg12–Atg5 conjugate functions as an E3-like enzyme to promote lipidation of Atg8, whereas lipidated Atg8 has essential roles in both autophagosome formation and selective cargo recognition during autophagy. However, the molecular role of Atg12 modification in these processes has remained elusive. Here, we report the crystal structure of the Atg12–Atg5 conjugate. In addition to the isopeptide linkage, Atg12 forms hydrophobic and hydrophilic interactions with Atg5, thereby fixing its position on Atg5. Structural comparison with unmodified Atg5 and mutational analyses showed that Atg12 modification neither induces a conformational change in Atg5 nor creates a functionally important architecture. Rather, Atg12 functions as a binding module for Atg3, the E2 enzyme for Atg8, thus endowing Atg5 with the ability to interact with Atg3 to facilitate Atg8 lipidation.
Nobuo N. Noda - One of the best experts on this subject based on the ideXlab platform.
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ATG7 Activates an Autophagy-Essential Ubiquitin-like Protein Atg8 through Multi-Step Recognition.
Journal of Molecular Biology, 2018Co-Authors: Masaya Yamaguchi, Hironori Suzuki, Yuko Fujioka, Fuyuhiko Inagaki, Yoshinori Ohsumi, Kenji Satoo, Nobuo N. NodaAbstract:Atg8 is a unique ubiquitin-like protein that is covalently conjugated with a phosphatidylethanolamine through reactions similar to ubiquitination and plays essential roles in autophagy. ATG7 is the E1 enzyme for Atg8, and it activates the C-terminal Gly116 of Atg8 using ATP. Here, we report the crystal structure of Atg8 bound to the C-terminal domain of ATG7 in an unprecedented mode. Atg8 neither contacts with the central β-sheet nor binds to the catalytic site of ATG7, both of which were observed in previously reported ATG7-Atg8 structures. Instead, Atg8 binds to the C-terminal α-helix and crossover loop, thereby changing the autoinhibited conformation of the crossover loop observed in the free ATG7 structure into a short helix and a disordered loop. Mutational analyses suggested that this interaction mode is important for the activation reaction. We propose that ATG7 recognizes Atg8 through multiple steps, which would be necessary to induce a conformational change in ATG7 that is optimal for the activation reaction.
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the intrinsically disordered protein atg13 mediates supramolecular assembly of autophagy initiation complexes
Developmental Cell, 2016Co-Authors: Hayashi Yamamoto, Daisuke Noshiro, Chika Kondokakuta, Hironori Suzuki, Yuko Fujioka, Sho Suzuki, Toshio Ando, Yayoi Kimura, Hisashi Hirano, Nobuo N. NodaAbstract:Autophagosome formation in yeast entails starvation-induced assembly of the pre-autophagosomal structure (PAS), in which multiple Atg1 complexes (composed of Atg1, Atg13, and the Atg17-Atg29-Atg31 subcomplex) are initially engaged. However, the molecular mechanisms underlying the multimeric assembly of these complexes remain unclear. Using structural and biological techniques, we herein demonstrate that Atg13 has a large intrinsically disordered region (IDR) and interacts with two distinct Atg17 molecules using two binding regions in the IDR. We further reveal that these two binding regions are essential not only for Atg1 complex assembly in vitro, but also for PAS organization in vivo. These findings underscore the structural and functional significance of the IDR of Atg13 in autophagy initiation: Atg13 provides intercomplex linkages between Atg17-Atg29-Atg31 complexes, thereby leading to supramolecular self-assembly of Atg1 complexes, in turn accelerating the initial events of autophagy, including autophosphorylation of Atg1, recruitment of Atg9 vesicles, and phosphorylation of Atg9 by Atg1.
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architecture of the atg12 atg5 atg16 complex and its molecular role in autophagy
Autophagy: Cancer Other Pathologies Inflammation Immunity Infection and Aging#R##N#Volume 3 - Mitophagy, 2014Co-Authors: Nobuo N. Noda, Fuyuhiko InagakiAbstract:Atg5 is covalently modified with Atg12 via reactions that are similar to ubiquitination, and it noncovalently interacts with Atg16. Formation of the Atg12–Atg5–Atg16 complex is essential for its E3-like function: facilitation of Atg8 transfer from Atg3 to phosphatidylethanolamine at autophagic membranes. Structural studies on the Atg12–Atg5–Atg16 complex revealed that the unique architecture of this protein complex is totally distinct from the other E3 enzymes. The Atg12–Atg5–Atg16 complex interacts directly with Atg3 via Atg12, and enhances the conjugase activity of Atg3 by rearranging its catalytic center, while it is targeted to the membranes via Atg5 and Atg16, and promotes the transfer of Atg8 from Atg3 to the membranes.
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atg12 atg5 conjugate enhances e2 activity of atg3 by rearranging its catalytic site
Nature Structural & Molecular Biology, 2013Co-Authors: Machiko Sakohnakatogawa, Eri Asai, Kazuaki Matoba, Junko Ishii, Nobuo N. Noda, Fuyuhiko Inagaki, Hiromi Kirisako, Hitoshi Nakatogawa, Yoshinori OhsumiAbstract:In the yeast autophagy system, the Atg12–Atg5 conjugate acts as an E3 to promote the E2 activity of Atg3, which conjugates Atg8 to phosphatidylethanolamine. Now structural and biochemical analyses reveal that Atg12–Atg5 induces a rearrangement in the catalytic center of Atg3, which employs a threonine residue in addition to the active cysteine to catalyze the conjugation reaction.
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Atg12–Atg5 conjugate enhances E2 activity of Atg3 by rearranging its catalytic site
Nature Structural & Molecular Biology, 2013Co-Authors: Machiko Sakoh-nakatogawa, Eri Asai, Kazuaki Matoba, Junko Ishii, Nobuo N. Noda, Fuyuhiko Inagaki, Hiromi Kirisako, Hitoshi Nakatogawa, Yoshinori OhsumiAbstract:In the yeast autophagy system, the Atg12–Atg5 conjugate acts as an E3 to promote the E2 activity of Atg3, which conjugates Atg8 to phosphatidylethanolamine. Now structural and biochemical analyses reveal that Atg12–Atg5 induces a rearrangement in the catalytic center of Atg3, which employs a threonine residue in addition to the active cysteine to catalyze the conjugation reaction.
Yuko Fujioka - One of the best experts on this subject based on the ideXlab platform.
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ATG7 Activates an Autophagy-Essential Ubiquitin-like Protein Atg8 through Multi-Step Recognition.
Journal of Molecular Biology, 2018Co-Authors: Masaya Yamaguchi, Hironori Suzuki, Yuko Fujioka, Fuyuhiko Inagaki, Yoshinori Ohsumi, Kenji Satoo, Nobuo N. NodaAbstract:Atg8 is a unique ubiquitin-like protein that is covalently conjugated with a phosphatidylethanolamine through reactions similar to ubiquitination and plays essential roles in autophagy. ATG7 is the E1 enzyme for Atg8, and it activates the C-terminal Gly116 of Atg8 using ATP. Here, we report the crystal structure of Atg8 bound to the C-terminal domain of ATG7 in an unprecedented mode. Atg8 neither contacts with the central β-sheet nor binds to the catalytic site of ATG7, both of which were observed in previously reported ATG7-Atg8 structures. Instead, Atg8 binds to the C-terminal α-helix and crossover loop, thereby changing the autoinhibited conformation of the crossover loop observed in the free ATG7 structure into a short helix and a disordered loop. Mutational analyses suggested that this interaction mode is important for the activation reaction. We propose that ATG7 recognizes Atg8 through multiple steps, which would be necessary to induce a conformational change in ATG7 that is optimal for the activation reaction.
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the intrinsically disordered protein atg13 mediates supramolecular assembly of autophagy initiation complexes
Developmental Cell, 2016Co-Authors: Hayashi Yamamoto, Daisuke Noshiro, Chika Kondokakuta, Hironori Suzuki, Yuko Fujioka, Sho Suzuki, Toshio Ando, Yayoi Kimura, Hisashi Hirano, Nobuo N. NodaAbstract:Autophagosome formation in yeast entails starvation-induced assembly of the pre-autophagosomal structure (PAS), in which multiple Atg1 complexes (composed of Atg1, Atg13, and the Atg17-Atg29-Atg31 subcomplex) are initially engaged. However, the molecular mechanisms underlying the multimeric assembly of these complexes remain unclear. Using structural and biological techniques, we herein demonstrate that Atg13 has a large intrinsically disordered region (IDR) and interacts with two distinct Atg17 molecules using two binding regions in the IDR. We further reveal that these two binding regions are essential not only for Atg1 complex assembly in vitro, but also for PAS organization in vivo. These findings underscore the structural and functional significance of the IDR of Atg13 in autophagy initiation: Atg13 provides intercomplex linkages between Atg17-Atg29-Atg31 complexes, thereby leading to supramolecular self-assembly of Atg1 complexes, in turn accelerating the initial events of autophagy, including autophosphorylation of Atg1, recruitment of Atg9 vesicles, and phosphorylation of Atg9 by Atg1.
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structure of the atg12 atg5 conjugate reveals a platform for stimulating atg8 pe conjugation
EMBO Reports, 2013Co-Authors: Nobuo N. Noda, Takao Hanada, Yuko Fujioka, Yoshinori Ohsumi, Fuyuhiko InagakiAbstract:Atg12 is conjugated to Atg5 through enzymatic reactions similar to ubiquitination. The Atg12–Atg5 conjugate functions as an E3-like enzyme to promote lipidation of Atg8, whereas lipidated Atg8 has essential roles in both autophagosome formation and selective cargo recognition during autophagy. However, the molecular role of Atg12 modification in these processes has remained elusive. Here, we report the crystal structure of the Atg12–Atg5 conjugate. In addition to the isopeptide linkage, Atg12 forms hydrophobic and hydrophilic interactions with Atg5, thereby fixing its position on Atg5. Structural comparison with unmodified Atg5 and mutational analyses showed that Atg12 modification neither induces a conformational change in Atg5 nor creates a functionally important architecture. Rather, Atg12 functions as a binding module for Atg3, the E2 enzyme for Atg8, thus endowing Atg5 with the ability to interact with Atg3 to facilitate Atg8 lipidation.
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Structure of the Atg12–Atg5 conjugate reveals a platform for stimulating Atg8–PE conjugation
EMBO Reports, 2012Co-Authors: Nobuo N. Noda, Takao Hanada, Yuko Fujioka, Yoshinori Ohsumi, Fuyuhiko InagakiAbstract:Atg12 is conjugated to Atg5 through enzymatic reactions similar to ubiquitination. The Atg12–Atg5 conjugate functions as an E3-like enzyme to promote lipidation of Atg8, whereas lipidated Atg8 has essential roles in both autophagosome formation and selective cargo recognition during autophagy. However, the molecular role of Atg12 modification in these processes has remained elusive. Here, we report the crystal structure of the Atg12–Atg5 conjugate. In addition to the isopeptide linkage, Atg12 forms hydrophobic and hydrophilic interactions with Atg5, thereby fixing its position on Atg5. Structural comparison with unmodified Atg5 and mutational analyses showed that Atg12 modification neither induces a conformational change in Atg5 nor creates a functionally important architecture. Rather, Atg12 functions as a binding module for Atg3, the E2 enzyme for Atg8, thus endowing Atg5 with the ability to interact with Atg3 to facilitate Atg8 lipidation.
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noncanonical recognition and ubl loading of distinct e2s by autophagy essential ATG7
Nature Structural & Molecular Biology, 2012Co-Authors: Masaya Yamaguchi, Hayashi Yamamoto, Kazuaki Matoba, Yuko Fujioka, Hitoshi Nakatogawa, Ryoko Sawada, Yoshihiro Kobashigawa, Hisashi Hoshida, Rinji Akada, Yoshinori OhsumiAbstract:The enzymes involved in autophagy-related UBL conjugation bear only passing resemblance to their counterparts in the better-known UBL conjugation pathways. New structural work provides insight into the mechanism by which the UBL proteins Atg8 and Atg12 are correctly charged by a single activating enzyme, ATG7, then transferred onto their cognate E2 proteins, Atg3 and Atg10, respectively.
Chi-ming Liang - One of the best experts on this subject based on the ideXlab platform.
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Recombinant protein rVP1 upregulates BECN1-independent autophagy, MAPK1/3 phosphorylation and MMP9 activity via WIPI1/WIPI2 to promote macrophage migration.
Autophagy, 2013Co-Authors: Chiao-chun Liao, Shu-mei Liang, Chi-ming LiangAbstract:The monocyte/macrophage is critical for regulating immune and antitumor responses. Recombinant capsid protein VP1 (rVP1) of foot-and-mouth disease virus induces apoptosis and inhibits migration/metastasis of cancer cells. Here, we explored the effects of rVP1 on macrophages. Our results showed that rVP1 increased LC3-related autophagosome formation via WIPI1 and WIPI2 in a BECN1-independent manner. rVP1 treatment increased macrophage migration that was attenuated by knockdown of ATG5, ATG7, WIPI1 or WIPI2 and was abolished when both WIPI1 and WIPI2 were depleted. Treatment of macrophages with rVP1 increased matrix metalloproteinase-9 (MMP9) activity and phosphorylated mitogen-activated protein kinase 1/3 (MAPK1/3), two major mediators of cell migration. Knockdown of WIPI1, WIPI2, ATG5 and ATG7 but not BECN1 attenuated the rVP1-mediated increase in MAPK1/3 phosphorylation and MMP9 activity. These results indicated that rVP1 upregulated autophagy, MAPK1/3 phosphorylation and MMP9 activity to promote macrophage migration, which was dependent on WIPI1, WIPI2, ATG5 and ATG7 but not BECN1.
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recombinant protein rvp1 upregulates becn1 independent autophagy mapk1 3 phosphorylation and mmp9 activity via wipi1 wipi2 to promote macrophage migration
Autophagy, 2013Co-Authors: Chiao-chun Liao, Shu-mei Liang, Chi-ming LiangAbstract:The monocyte/macrophage is critical for regulating immune and antitumor responses. Recombinant capsid protein VP1 (rVP1) of foot-and-mouth disease virus induces apoptosis and inhibits migration/metastasis of cancer cells. Here, we explored the effects of rVP1 on macrophages. Our results showed that rVP1 increased LC3-related autophagosome formation via WIPI1 and WIPI2 in a BECN1-independent manner. rVP1 treatment increased macrophage migration that was attenuated by knockdown of ATG5, ATG7, WIPI1 or WIPI2 and was abolished when both WIPI1 and WIPI2 were depleted. Treatment of macrophages with rVP1 increased matrix metalloproteinase-9 (MMP9) activity and phosphorylated mitogen-activated protein kinase 1/3 (MAPK1/3), two major mediators of cell migration. Knockdown of WIPI1, WIPI2, ATG5 and ATG7 but not BECN1 attenuated the rVP1-mediated increase in MAPK1/3 phosphorylation and MMP9 activity. These results indicated that rVP1 upregulated autophagy, MAPK1/3 phosphorylation and MMP9 activity to promote macrophage migration, which was dependent on WIPI1, WIPI2, ATG5 and ATG7 but not BECN1.
