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Philipp Wild,
Hesso Farhan,
David G McEwan,
Sebastian Wagner,
Vladimir V Rogov,
Nathan R Brady,
Benjamin Richter,
Jelena Korac,
Oliver Waidmann,
Chunaram Choudhary,
Volker Dötsch,
Dirk Bumann,
Ivan Dikic
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ABSTRACT: Selective autophagy can be mediated via receptor molecules that link specific cargoes to the autophagosomal membranes decorated by ubiquitin-like microtubule-associated protein light chain 3 (LC3) modifiers. Although several autophagy receptors have been identified, little is known about mechanisms controlling their functions in vivo. In this work, we found that phosphorylation of an autophagy receptor, optineurin, promoted selective autophagy of ubiquitin-coated cytosolic Salmonella enterica. The protein kinase TANK binding kinase 1 (TBK1) phosphorylated optineurin on serine-177, enhancing LC3 binding affinity and autophagic clearance of cytosolic Salmonella. Conversely, ubiquitin- or LC3-binding optineurin mutants and silencing of optineurin or TBK1 impaired Salmonella autophagy, resulting in increased intracellular bacterial proliferation. We propose that phosphorylation of autophagy receptors might be a general mechanism for regulation of cargo-selective autophagy.
Science 05/2011; 333(6039):228-33. · 31.20 Impact Factor
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ABSTRACT: Dysfunctional mitochondria show a reduced capacity for fusion and, as mitochondrial fission is maintained, become spatially separated from the intact network. By that mechanism, dysfunctional mitochondria have been proposed to be targeted for selective degradation by mitophagy, thereby providing a quality control system for mitochondria. In yeast, conflicting results concerning the role of mitochondrial dynamics in mitophagy have been reported. Here, we investigate the effects on mitophagy of altering mitochondrial fission and fusion, using biochemical, as well as fluorescence-based, assays. Rapamycin-induced mitophagy was shown to depend upon the autophagy-related proteins Atg11, Atg20 and Atg24, confirming that a selective type of autophagy occurred. Both fragmentation of mitochondria and inhibition of oxidative phosphorylation were not sufficient to trigger mitophagy, and neither deletion of the fission factors Dnm1, Fis1, Mdv1 or Caf4 nor expression of dominant-negative variants of Dnm1 impaired mitophagy. The diminished mitophagy initially observed in a Δfis1 mutant was not due to the absence of Fis1 but rather due to a secondary mutation in WHI2, which encodes a factor reported to function in the general stress response and the Ras-protein kinase A (PKA) signaling pathway. We propose that, in yeast, mitochondrial fission is not a prerequisite for the selective degradation of mitochondria, and that mitophagy is linked to the general stress response and the Ras-PKA signaling pathway.
Journal of Cell Science 03/2011; 124(Pt 8):1339-50. · 6.11 Impact Factor
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ABSTRACT: Recent studies have revealed a prominent role of mitochondrial dysfunction in the development of one of the most common neurodegenerative disorders, Parkinson's disease. The ubiquitin ligase Parkin and the protein kinase PINK1, whose mutations are associated with Parkinson's disease, function in a pathway that links ubiquitylation with selective autophagy of damaged mitochondria.
Nature Cell Biology 02/2010; 12(2):104-6. · 19.49 Impact Factor
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Ivana Novak,
Vladimir Kirkin,
David G McEwan,
Ji Zhang, Philipp Wild,
Alexis Rozenknop,
Vladimir Rogov,
Frank Löhr,
Doris Popovic,
Angelo Occhipinti,
Andreas S Reichert,
Janos Terzic,
Volker Dötsch,
Paul A Ney,
Ivan Dikic
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ABSTRACT: Autophagy is the cellular homeostatic pathway that delivers large cytosolic materials for degradation in the lysosome. Recent evidence indicates that autophagy mediates selective removal of protein aggregates, organelles and microbes in cells. Yet, the specificity in targeting a particular substrate to the autophagy pathway remains poorly understood. Here, we show that the mitochondrial protein Nix is a selective autophagy receptor by binding to LC3/GABARAP proteins, ubiquitin-like modifiers that are required for the growth of autophagosomal membranes. In cultured cells, Nix recruits GABARAP-L1 to damaged mitochondria through its amino-terminal LC3-interacting region. Furthermore, ablation of the Nix:LC3/GABARAP interaction retards mitochondrial clearance in maturing murine reticulocytes. Thus, Nix functions as an autophagy receptor, which mediates mitochondrial clearance after mitochondrial damage and during erythrocyte differentiation.
EMBO Reports 12/2009; 11(1):45-51. · 7.36 Impact Factor
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Vladimir Kirkin,
Trond Lamark,
Yu-Shin Sou,
Geir Bjørkøy,
Jennifer L Nunn,
Jack-Ansgar Bruun,
Elena Shvets,
David G McEwan,
Terje H Clausen, Philipp Wild,
Ivana Bilusic,
Jean-Philippe Theurillat,
Aud Øvervatn,
Tetsuro Ishii,
Zvulun Elazar,
Masaaki Komatsu,
Ivan Dikic,
Terje Johansen
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ABSTRACT: Autophagy is a catabolic process where cytosolic cellular components are delivered to the lysosome for degradation. Recent studies have indicated the existence of specific receptors, such as p62, which link ubiquitinated targets to autophagosomal degradation pathways. Here we show that NBR1 (neighbor of BRCA1 gene 1) is an autophagy receptor containing LC3- and ubiquitin (Ub)-binding domains. NBR1 is recruited to Ub-positive protein aggregates and degraded by autophagy depending on an LC3-interacting region (LIR) and LC3 family modifiers. Although NBR1 and p62 interact and form oligomers, they can function independently, as shown by autophagosomal clearance of NBR1 in p62-deficient cells. NBR1 was localized to Ub-positive inclusions in patients with liver dysfunction, and depletion of NBR1 abolished the formation of Ub-positive p62 bodies upon puromycin treatment of cells. We propose that NBR1 and p62 act as receptors for selective autophagosomal degradation of ubiquitinated targets.
Molecular cell 03/2009; 33(4):505-16. · 14.61 Impact Factor
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Yonathan Lissanu Deribe, Philipp Wild,
Akhila Chandrashaker,
Jasna Curak,
Mirko H H Schmidt,
Yannis Kalaidzidis,
Natasa Milutinovic,
Irina Kratchmarova,
Lukas Buerkle,
Michael J Fetchko,
Philipp Schmidt,
Saranya Kittanakom,
Kevin R Brown,
Igor Jurisica,
Blagoy Blagoev,
Marino Zerial,
Igor Stagljar,
Ivan Dikic
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ABSTRACT: Binding of epidermal growth factor (EGF) to its receptor leads to receptor dimerization, assembly of protein complexes, and activation of signaling networks that control key cellular responses. Despite their fundamental role in cell biology, little is known about protein complexes associated with the EGF receptor (EGFR) before growth factor stimulation. We used a modified membrane yeast two-hybrid system together with bioinformatics to identify 87 candidate proteins interacting with the ligand-unoccupied EGFR. Among them was histone deacetylase 6 (HDAC6), a cytoplasmic lysine deacetylase, which we found negatively regulated EGFR endocytosis and degradation by controlling the acetylation status of alpha-tubulin and, subsequently, receptor trafficking along microtubules. A negative feedback loop consisting of EGFR-mediated phosphorylation of HDAC6 Tyr(570) resulted in reduced deacetylase activity and increased acetylation of alpha-tubulin. This study illustrates the complexity of the EGFR-associated interactome and identifies protein acetylation as a previously unknown regulator of receptor endocytosis and degradation.
Science Signaling 01/2009; 2(102):ra84. · 7.50 Impact Factor
