2.50
Hdl Handle:
http://hdl.handle.net/10033/293134
Title:
Phosphorylation of Atg5 by the Gadd45β-MEKK4-p38 pathway inhibits autophagy.
Authors:
Keil, E; Höcker, R; Schuster, M; Essmann, F; Ueffing, N; Hoffman, B; Liebermann, D A; Pfeffer, K; Schulze-Osthoff, K; Schmitz, I
Abstract:
Autophagy is a lysosomal degradation pathway important for cellular homeostasis, mammalian development, cancer and immunity. Many molecular components of autophagy have been identified, but little is known about regulatory mechanisms controlling their effector functions. Here, we show that, in contrast to other p38 MAP kinase activators, the growth arrest and DNA damage 45 beta (Gadd45β)-MAPK/ERK kinase kinase 4 (MEKK4) pathway specifically directs p38 to autophagosomes. This process results in an accumulation of autophagosomes through p38-mediated inhibition of lysosome fusion. Conversely, autophagic flux is increased in p38-deficient fibroblasts and Gadd45β-deficient cells. We further identified the underlying mechanism and demonstrate that phosphorylation of the autophagy regulator autophagy-related (Atg)5 at threonine 75 through p38 is responsible for inhibition of starvation-induced autophagy. Thus, we show for the first time that Atg5 activity is controlled by phosphorylation and, moreover, that the spatial regulation of p38 by Gadd45β/MEKK4 negatively regulates the autophagic process.
Affiliation:
Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University, Universitätsstr. 1, Düsseldorf, Germany.
Citation:
Phosphorylation of Atg5 by the Gadd45β-MEKK4-p38 pathway inhibits autophagy. 2013, 20 (2):321-32 Cell Death Differ.
Journal:
Cell death and differentiation
Issue Date:
Feb-2013
URI:
http://hdl.handle.net/10033/293134
DOI:
10.1038/cdd.2012.129
PubMed ID:
23059785
Type:
Article
Language:
en
ISSN:
1476-5403
Appears in Collections:
publications of the AG system-oriented immunologyand infection research (SIME)

Full metadata record

DC FieldValue Language
dc.contributor.authorKeil, Een_GB
dc.contributor.authorHöcker, Ren_GB
dc.contributor.authorSchuster, Men_GB
dc.contributor.authorEssmann, Fen_GB
dc.contributor.authorUeffing, Nen_GB
dc.contributor.authorHoffman, Ben_GB
dc.contributor.authorLiebermann, D Aen_GB
dc.contributor.authorPfeffer, Ken_GB
dc.contributor.authorSchulze-Osthoff, Ken_GB
dc.contributor.authorSchmitz, Ien_GB
dc.date.accessioned2013-05-31T11:53:16Z-
dc.date.available2013-05-31T11:53:16Z-
dc.date.issued2013-02-
dc.identifier.citationPhosphorylation of Atg5 by the Gadd45β-MEKK4-p38 pathway inhibits autophagy. 2013, 20 (2):321-32 Cell Death Differ.en_GB
dc.identifier.issn1476-5403-
dc.identifier.pmid23059785-
dc.identifier.doi10.1038/cdd.2012.129-
dc.identifier.urihttp://hdl.handle.net/10033/293134-
dc.description.abstractAutophagy is a lysosomal degradation pathway important for cellular homeostasis, mammalian development, cancer and immunity. Many molecular components of autophagy have been identified, but little is known about regulatory mechanisms controlling their effector functions. Here, we show that, in contrast to other p38 MAP kinase activators, the growth arrest and DNA damage 45 beta (Gadd45β)-MAPK/ERK kinase kinase 4 (MEKK4) pathway specifically directs p38 to autophagosomes. This process results in an accumulation of autophagosomes through p38-mediated inhibition of lysosome fusion. Conversely, autophagic flux is increased in p38-deficient fibroblasts and Gadd45β-deficient cells. We further identified the underlying mechanism and demonstrate that phosphorylation of the autophagy regulator autophagy-related (Atg)5 at threonine 75 through p38 is responsible for inhibition of starvation-induced autophagy. Thus, we show for the first time that Atg5 activity is controlled by phosphorylation and, moreover, that the spatial regulation of p38 by Gadd45β/MEKK4 negatively regulates the autophagic process.en_GB
dc.language.isoenen
dc.rightsArchived with thanks to Cell death and differentiationen_GB
dc.titlePhosphorylation of Atg5 by the Gadd45β-MEKK4-p38 pathway inhibits autophagy.en
dc.typeArticleen
dc.contributor.departmentInstitute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University, Universitätsstr. 1, Düsseldorf, Germany.en_GB
dc.identifier.journalCell death and differentiationen_GB

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