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Article ; Online: A heterodimeric SNX4--SNX7 SNX-BAR autophagy complex coordinates ATG9A trafficking for efficient autophagosome assembly.

Antón, Zuriñe / Betin, Virginie M S / Simonetti, Boris / Traer, Colin J / Attar, Naomi / Cullen, Peter J / Lane, Jon D

2020 Volume 133, Issue 14

Abstract: The sorting nexins (SNXs) are a family of peripheral membrane proteins that direct protein trafficking decisions within the endocytic network. Emerging evidence in yeast and mammalian cells implicates a subgroup of SNXs in selective and non-selective ... ...

Abstract	The sorting nexins (SNXs) are a family of peripheral membrane proteins that direct protein trafficking decisions within the endocytic network. Emerging evidence in yeast and mammalian cells implicates a subgroup of SNXs in selective and non-selective forms of autophagy. Using siRNA and CRISPR-Cas9, we demonstrate that the SNX-BAR protein SNX4 is needed for efficient LC3 (also known as MAP1LC3) lipidation and autophagosome assembly in mammalian cells. SNX-BARs exist as homo- and hetero-dimers, and we show that SNX4 forms functional heterodimers with either SNX7 or SNX30 that associate with tubulovesicular endocytic membranes. Detailed image-based analysis during the early stages of autophagosome assembly reveals that SNX4-SNX7 is an autophagy-specific SNX-BAR heterodimer, required for efficient recruitment and/or retention of core autophagy regulators at the nascent isolation membrane. SNX4 partially colocalises with juxtanuclear ATG9A-positive membranes, with our data linking the autophagy defect upon SNX4 disruption to the mis-trafficking and/or retention of ATG9A in the Golgi region. Taken together, our findings show that the SNX4-SNX7 heterodimer coordinates ATG9A trafficking within the endocytic network to establish productive autophagosome assembly sites, thus extending knowledge of SNXs as positive regulators of autophagy.
MeSH term(s)	Animals ; Autophagosomes/metabolism ; Autophagy ; Endosomes/metabolism ; Protein Transport ; Sorting Nexins/genetics ; Sorting Nexins/metabolism
Chemical Substances	Sorting Nexins
Language	English
Publishing date	2020-07-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2993-2
ISSN	1477-9137 ; 0021-9533
ISSN (online)	1477-9137
ISSN	0021-9533
DOI	10.1242/jcs.246306
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Article: Caspase cleavage of Atg4D stimulates GABARAP-L1 processing and triggers mitochondrial targeting and apoptosis.

Betin, Virginie M S / Lane, Jon D

Journal of cell science

2009 Volume 122, Issue Pt 14, Page(s) 2554–2566

Abstract: Autophagy is an important catabolic process with roles in cell survival and cell death. It sequesters cytosol and organelles within double-membrane autophagosomes that deliver their contents to lysosomes for degradation. Autophagosome biogenesis is ... ...

Abstract	Autophagy is an important catabolic process with roles in cell survival and cell death. It sequesters cytosol and organelles within double-membrane autophagosomes that deliver their contents to lysosomes for degradation. Autophagosome biogenesis is coordinated by the autophagy-related protein 4 (Atg4) family of C54 endopeptidases (Atg4A-Atg4D). These enzymes prime and then later delipidate the autophagosome marker, Atg8. Here, we show that one family member, Atg4D, is cleaved by caspase-3 in vitro and in apoptotic cells. Atg4D is a poor priming and delipidation enzyme in vitro, but truncated DeltaN63 Atg4D displays increased activity against the Atg8 paralogue, gamma-aminobutyric acid receptor-associated protein-like 1 (GABARAP-L1). In living cells, DeltaN63 Atg4D stimulates the delipidation of GABARAP-L1, whereas siRNA silencing of the gene expressing Atg4D abrogates GABARAP-L1 autophagosome formation and sensitises cells to starvation and staurosporine-induced cell death. Interestingly, Atg4D overexpression induces apoptosis, which is preceded by the caspase-independent recruitment of Atg4D to mitochondria and is facilitated by a putative C-terminal Bcl-2 homology 3 (BH3) domain. Atg4D also acquires affinity for damaged mitochondria in cells treated with hydrogen peroxide. These data suggest that Atg4D is an autophagy regulator that links mitochondrial dysfunction with apoptosis.
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Amino Acid Sequence ; Apoptosis/drug effects ; Autophagy/drug effects ; Autophagy-Related Proteins ; Caspase 3/metabolism ; Cysteine Endopeptidases/genetics ; Cysteine Endopeptidases/metabolism ; HeLa Cells ; Humans ; Hydrogen Peroxide/pharmacology ; Lipid Metabolism ; Microtubule-Associated Proteins/genetics ; Microtubule-Associated Proteins/metabolism ; Mitochondria/drug effects ; Mitochondria/enzymology ; Mitochondria/pathology ; Molecular Sequence Data ; Mutation ; Oxidative Stress ; Protein Structure, Tertiary ; RNA Interference ; Signal Transduction/drug effects ; Staurosporine/pharmacology ; Stress, Physiological/drug effects ; Time Factors ; Transfection
Chemical Substances	Adaptor Proteins, Signal Transducing ; Autophagy-Related Proteins ; GABARAPL1 protein, human ; Microtubule-Associated Proteins ; Hydrogen Peroxide (BBX060AN9V) ; ATG4B protein, human (EC 3.4.22.-) ; ATG4D protein, human (EC 3.4.22.-) ; CASP3 protein, human (EC 3.4.22.-) ; Caspase 3 (EC 3.4.22.-) ; Cysteine Endopeptidases (EC 3.4.22.-) ; Staurosporine (H88EPA0A3N)
Language	English
Publishing date	2009-06-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2993-2
ISSN	1477-9137 ; 0021-9533
ISSN (online)	1477-9137
ISSN	0021-9533
DOI	10.1242/jcs.046250
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Article ; Online: Atg4D at the interface between autophagy and apoptosis.

Betin, Virginie M S / Lane, Jon D

Autophagy

2009 Volume 5, Issue 7, Page(s) 1057–1059

Abstract: The Atg4 family of endopeptidases regulates autophagosome biogenesis by priming newly synthesized Atg8 to enable covalent attachment of phosphatidylethanolamine, and by delipidating Atg8 at the lysosomal fusion step. Control of Atg4 activity is therefore ...

Abstract	The Atg4 family of endopeptidases regulates autophagosome biogenesis by priming newly synthesized Atg8 to enable covalent attachment of phosphatidylethanolamine, and by delipidating Atg8 at the lysosomal fusion step. Control of Atg4 activity is therefore crucial, although little is known about how these molecules are regulated in living cells. We have found that one human Atg4 family member (Atg4D) is cleaved at DEVD(63)K by caspase-3 during apoptosis. Importantly, our studies suggest that native Atg4D is enzymatically inactive, but gains GABARAP-L1 priming/delipidation activity following caspase cleavage. Caspase-cleaved Atg4D is also highly cytotoxic; however, toxicity is not due to enhanced autophagy, but is mediated by a putative C-terminal BH3 domain, and is associated with transient recruitment of Atg4D to mitochondria.
MeSH term(s)	Apoptosis/physiology ; Apoptosis Regulatory Proteins/metabolism ; Autophagy/physiology ; Autophagy-Related Proteins ; Beclin-1 ; Cysteine Endopeptidases/metabolism ; Humans ; Membrane Proteins/metabolism
Chemical Substances	Apoptosis Regulatory Proteins ; Autophagy-Related Proteins ; BECN1 protein, human ; Beclin-1 ; Membrane Proteins ; ATG4D protein, human (EC 3.4.22.-) ; Cysteine Endopeptidases (EC 3.4.22.-)
Language	English
Publishing date	2009-10-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.4161/auto.5.7.9684
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Article: Caspase cleavage of Atg4D stimulates GABARAP-L1 processing and triggers mitochondrial targeting and apoptosis

Betin, Virginie M.S / Lane, Jon D

Journal of cell science. 2009 July 15, v. 122, no. 14

2009

Abstract	Autophagy is an important catabolic process with roles in cell survival and cell death. It sequesters cytosol and organelles within double-membrane autophagosomes that deliver their contents to lysosomes for degradation. Autophagosome biogenesis is coordinated by the autophagy-related protein 4 (Atg4) family of C54 endopeptidases (Atg4A-Atg4D). These enzymes prime and then later delipidate the autophagosome marker, Atg8. Here, we show that one family member, Atg4D, is cleaved by caspase-3 in vitro and in apoptotic cells. Atg4D is a poor priming and delipidation enzyme in vitro, but truncated ΔN63 Atg4D displays increased activity against the Atg8 paralogue, γ-aminobutyric acid receptor-associated protein-like 1 (GABARAP-L1). In living cells, ΔN63 Atg4D stimulates the delipidation of GABARAP-L1, whereas siRNA silencing of the gene expressing Atg4D abrogates GABARAP-L1 autophagosome formation and sensitises cells to starvation and staurosporine-induced cell death. Interestingly, Atg4D overexpression induces apoptosis, which is preceded by the caspase-independent recruitment of Atg4D to mitochondria and is facilitated by a putative C-terminal Bcl-2 homology 3 (BH3) domain. Atg4D also acquires affinity for damaged mitochondria in cells treated with hydrogen peroxide. These data suggest that Atg4D is an autophagy regulator that links mitochondrial dysfunction with apoptosis.
Language	English
Dates of publication	2009-0715
Size	p. 2554-2566.
Publishing place	The Company of Biologists Limited
Document type	Article
ZDB-ID	2993-2
ISSN	1477-9137 ; 0021-9533
ISSN (online)	1477-9137
ISSN	0021-9533
Database	NAL-Catalogue (AGRICOLA)

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Article: The cytoskeleton and the control of organelle dynamics in the apoptotic execution phase.

Betin, Virginie M S / Lane, Jon D

SEB experimental biology series

2008 Volume 59, Page(s) 267–289

MeSH term(s)	Apoptosis/physiology ; Caspases/metabolism ; Cell Cycle/physiology ; Cell Surface Extensions/metabolism ; Cytoskeleton/metabolism ; Enzyme Activation ; Microtubules/metabolism ; Organelles/metabolism ; Signal Transduction/physiology
Chemical Substances	Caspases (EC 3.4.22.-)
Language	English
Publishing date	2008
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1946-4959
ISSN	1946-4959
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Article ; Online: Autophagy facilitates organelle clearance during differentiation of human erythroblasts: evidence for a role for ATG4 paralogs during autophagosome maturation.

Betin, Virginie M S / Singleton, Belinda K / Parsons, Stephen F / Anstee, David J / Lane, Jon D

Autophagy

2013 Volume 9, Issue 6, Page(s) 881–893

Abstract: Wholesale depletion of membrane organelles and extrusion of the nucleus are hallmarks of mammalian erythropoiesis. Using quantitative EM and fluorescence imaging we have investigated how autophagy contributes to organelle removal in an ex vivo model of ... ...

Abstract	Wholesale depletion of membrane organelles and extrusion of the nucleus are hallmarks of mammalian erythropoiesis. Using quantitative EM and fluorescence imaging we have investigated how autophagy contributes to organelle removal in an ex vivo model of human erythroid differentiation. We found that autophagy is induced at the polychromatic erythroid stage, and that autophagosomes remain abundant until enucleation. This stimulation of autophagy was concomitant with the transcriptional upregulation of many autophagy genes: of note, expression of all ATG8 mammalian paralog family members was stimulated, and increased expression of a subset of ATG4 family members (ATG4A and ATG4D) was also observed. Stable expression of dominant-negative ATG4 cysteine mutants (ATG4B (C74A) ATG4D (C144A) ) did not markedly delay or accelerate differentiation of human erythroid cells; however, quantitative EM demonstrated that autophagosomes are assembled less efficiently in ATG4B (C74A) -expressing progenitor cells, and that cells expressing either mutant accumulate enlarged amphisomes that cannot be degraded. The appearance of these hybrid autophagosome/endosome structures correlated with the contraction of the lysosomal compartment, suggesting that the actions of ATG4 family members (particularly ATG4B) are required for the control of autophagosome fusion with late, degradative compartments in differentiating human erythroblasts.
MeSH term(s)	Autophagy ; Autophagy-Related Proteins ; Cell Compartmentation ; Cell Differentiation ; Cysteine/genetics ; Cysteine Endopeptidases/metabolism ; Erythroblasts/cytology ; Erythroblasts/metabolism ; Erythroblasts/ultrastructure ; HEK293 Cells ; HeLa Cells ; Humans ; Intracellular Membranes/metabolism ; Intracellular Membranes/ultrastructure ; Mitochondria/metabolism ; Mitochondria/ultrastructure ; Mutant Proteins/metabolism ; Phagosomes/metabolism ; Phagosomes/ultrastructure ; Sequence Homology, Amino Acid ; Up-Regulation
Chemical Substances	Autophagy-Related Proteins ; Mutant Proteins ; ATG4A protein, human (EC 3.4.22.-) ; ATG4B protein, human (EC 3.4.22.-) ; ATG4D protein, human (EC 3.4.22.-) ; Cysteine Endopeptidases (EC 3.4.22.-) ; Cysteine (K848JZ4886)
Language	English
Publishing date	2013-03-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.4161/auto.24172
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Article ; Online: Enhanced insulin receptor, but not PI3K, signalling protects podocytes from ER stress.

Garner, Kathryn L / Betin, Virginie M S / Pinto, Vanda / Graham, Mark / Abgueguen, Emmanuelle / Barnes, Matt / Bedford, David C / McArdle, Craig A / Coward, Richard J M

Scientific reports

2018 Volume 8, Issue 1, Page(s) 3902

Abstract: Disruption of the insulin-PI3K-Akt signalling pathway in kidney podocytes causes endoplasmic reticulum (ER) stress, leading to podocyte apoptosis and proteinuria in diabetic nephropathy. We hypothesised that by improving insulin sensitivity we could ... ...

Abstract	Disruption of the insulin-PI3K-Akt signalling pathway in kidney podocytes causes endoplasmic reticulum (ER) stress, leading to podocyte apoptosis and proteinuria in diabetic nephropathy. We hypothesised that by improving insulin sensitivity we could protect podocytes from ER stress. Here we use established activating transcription factor 6 (ATF6)- and ER stress element (ERSE)-luciferase assays alongside a novel high throughput imaging-based C/EBP homologous protein (CHOP) assay to examine three models of improved insulin sensitivity. We find that by improving insulin sensitivity at the level of the insulin receptor (IR), either by IR over-expression or by knocking down the negative regulator of IR activity, protein tyrosine-phosphatase 1B (PTP1B), podocytes are protected from ER stress caused by fatty acids or diabetic media containing high glucose, high insulin and inflammatory cytokines TNFα and IL-6. However, contrary to this, knockdown of the negative regulator of PI3K-Akt signalling, phosphatase and tensin homolog deleted from chromosome 10 (PTEN), sensitizes podocytes to ER stress and apoptosis, despite increasing Akt phosphorylation. This indicates that protection from ER stress is conferred through not just the PI3K-Akt pathway, and indeed we find that inhibiting the MEK/ERK signalling pathway rescues PTEN knockdown podocytes from ER stress.
MeSH term(s)	Animals ; Apoptosis ; Cells, Cultured ; Endoplasmic Reticulum Stress ; Insulin/metabolism ; Mice ; PTEN Phosphohydrolase/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphorylation ; Podocytes/cytology ; Podocytes/physiology ; Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism ; Receptor, Insulin/metabolism ; Signal Transduction
Chemical Substances	Insulin ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Receptor, Insulin (EC 2.7.10.1) ; Protein Tyrosine Phosphatase, Non-Receptor Type 1 (EC 3.1.3.48) ; Ptpn1 protein, mouse (EC 3.1.3.48) ; PTEN Phosphohydrolase (EC 3.1.3.67) ; Pten protein, mouse (EC 3.1.3.67)
Language	English
Publishing date	2018-03-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-018-22233-9
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Article ; Online: Prolonged exposure of mouse and human podocytes to insulin induces insulin resistance through lysosomal and proteasomal degradation of the insulin receptor.

Lay, Abigail C / Hurcombe, Jenny A / Betin, Virginie M S / Barrington, Fern / Rollason, Ruth / Ni, Lan / Gillam, Lawrence / Pearson, Grace M E / Østergaard, Mette V / Hamidi, Hellyeh / Lennon, Rachel / Welsh, Gavin I / Coward, Richard J M

Diabetologia

2017 Volume 60, Issue 11, Page(s) 2299–2311

Abstract: Aims/hypothesis: Podocytes are insulin-responsive cells of the glomerular filtration barrier and are key in preventing albuminuria, a hallmark feature of diabetic nephropathy. While there is evidence that a loss of insulin signalling to podocytes is ... ...

Abstract	Aims/hypothesis: Podocytes are insulin-responsive cells of the glomerular filtration barrier and are key in preventing albuminuria, a hallmark feature of diabetic nephropathy. While there is evidence that a loss of insulin signalling to podocytes is detrimental, the molecular mechanisms underpinning the development of podocyte insulin resistance in diabetes remain unclear. Thus, we aimed to further investigate podocyte insulin responses early in the context of diabetic nephropathy. Methods: Conditionally immortalised human and mouse podocyte cell lines and glomeruli isolated from db/db DBA/2J mice were studied. Podocyte insulin responses were investigated with western blotting, cellular glucose uptake assays and automated fluorescent imaging of the actin cytoskeleton. Quantitative (q)RT-PCR was employed to investigate changes in mRNA. Human cell lines stably overproducing the insulin receptor (IR) and nephrin were also generated, using lentiviral constructs. Results: Podocytes exposed to a diabetic environment (high glucose, high insulin and the proinflammatory cytokines TNF-α and IL-6) become insulin resistant with respect to glucose uptake and activation of phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signalling. These podocytes lose expression of the IR as a direct consequence of prolonged exposure to high insulin concentrations, which causes an increase in IR protein degradation via a proteasome-dependent and bafilomycin-sensitive pathway. Reintroducing the IR into insulin-resistant human podocytes rescues upstream phosphorylation events, but not glucose uptake. Stable expression of nephrin is also required for the insulin-stimulated glucose uptake response in podocytes and for efficient insulin-stimulated remodelling of the actin cytoskeleton. Conclusions/interpretation: Together, these results suggest that IR degradation, caused by high levels of insulin, drives early podocyte insulin resistance, and that both the IR and nephrin are required for full insulin sensitivity of this cell. This could be highly relevant for the development of nephropathy in individuals with type 2 diabetes, who are commonly hyperinsulinaemic in the early phases of their disease.
MeSH term(s)	Animals ; Blotting, Western ; Cells, Cultured ; Diabetic Nephropathies/metabolism ; Humans ; Immunoprecipitation ; Insulin/pharmacology ; Insulin Resistance/physiology ; Male ; Mice ; Podocytes/drug effects ; Podocytes/metabolism ; Receptor, Insulin/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/drug effects
Chemical Substances	Insulin ; Receptor, Insulin (EC 2.7.10.1)
Language	English
Publishing date	2017-08-29
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1694-9
ISSN	1432-0428 ; 0012-186X
ISSN (online)	1432-0428
ISSN	0012-186X
DOI	10.1007/s00125-017-4394-0
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Article: A novel role for microtubules in apoptotic chromatin dynamics and cellular fragmentation.

Moss, David K / Betin, Virginie M / Malesinski, Soazig D / Lane, Jon D

Journal of cell science

2006 Volume 119, Issue Pt 11, Page(s) 2362–2374

Abstract: Dramatic changes in cellular dynamics characterise the apoptotic execution phase, culminating in fragmentation into membrane-bound apoptotic bodies. Previous evidence suggests that actin-myosin plays a dominant role in apoptotic cellular remodelling, ... ...

Abstract	Dramatic changes in cellular dynamics characterise the apoptotic execution phase, culminating in fragmentation into membrane-bound apoptotic bodies. Previous evidence suggests that actin-myosin plays a dominant role in apoptotic cellular remodelling, whereas all other cytoskeletal elements dismantle. We have used fixed cells and live-cell imaging to confirm that interphase microtubules rapidly depolymerise at the start of the execution phase. Around this time, pericentriolar components (pericentrin, ninein and gamma-tubulin) are lost from the centrosomal region. Subsequently, however, extensive non-centrosomal bundles of densely packed, dynamic microtubules rapidly assemble throughout the cytoplasm in all cell lines tested. These microtubules have an important role in the peripheral relocation of chromatin in the dying cell, because nocodazole treatment restricts the dispersal of condensed apoptotic chromatin into surface blebs, and causes the withdrawal of chromatin fragments back towards the cell centre. Importantly, nocodazole and taxol are both potent inhibitors of apoptotic fragmentation in A431 cells, implicating dynamic microtubules in apoptotic body formation. Live-cell-imaging studies indicate that fragmentation is accompanied by the extension of rigid microtubule-rich spikes that project through the cortex of the dying cell. These structures enhance interactions between apoptotic cells and phagocytes in vitro, by providing additional sites for attachment to neighbouring cells.
MeSH term(s)	Anisomycin/pharmacology ; Apoptosis/drug effects ; Apoptosis/physiology ; Apoptosis/radiation effects ; Cell Line ; Chromatin/metabolism ; HeLa Cells ; Humans ; Macrophages/metabolism ; Microscopy, Fluorescence/methods ; Microtubules/physiology ; Ultraviolet Rays
Chemical Substances	Chromatin ; Anisomycin (6C74YM2NGI)
Language	English
Publishing date	2006-05-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2993-2
ISSN	1477-9137 ; 0021-9533
ISSN (online)	1477-9137
ISSN	0021-9533
DOI	10.1242/jcs.02959
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Article ; Online: A cryptic mitochondrial targeting motif in Atg4D links caspase cleavage with mitochondrial import and oxidative stress.

Betin, Virginie M S / MacVicar, Thomas D B / Parsons, Stephen F / Anstee, David J / Lane, Jon D

Autophagy

2012 Volume 8, Issue 4, Page(s) 664–676

Abstract: The Atg4 cysteine proteases play crucial roles in the processing of Atg8 proteins during autophagy, but their regulation during cellular stress and differentiation remains poorly understood. We have found that two Atg4 family members--Atg4C and Atg4D-- ... ...

Abstract	The Atg4 cysteine proteases play crucial roles in the processing of Atg8 proteins during autophagy, but their regulation during cellular stress and differentiation remains poorly understood. We have found that two Atg4 family members--Atg4C and Atg4D--contain cryptic mitochondrial targeting sequences immediately downstream of their canonical (DEVD) caspase cleavage sites. Consequently, caspase-cleaved Atg4D (ΔN63 Atg4D) localizes to the mitochondrial matrix when expressed in mammalian cells, where it undergoes further processing to a ~42 kDa mitochondrial form. Interestingly, caspase cleavage is not needed for Atg4D mitochondrial import, because ~42 kDa mitochondrial Atg4D is observed in cells treated with caspase inhibitors and in cells expressing caspase-resistant Atg4D (DEVA(63)). Using HeLa cell lines stably expressing ΔN63 Atg4D, we showed that mitochondrial Atg4D sensitizes cells to cell death in the presence of the mitochondrial uncoupler, CCCP, and that mitochondrial cristae are less extensive in these cells. We further showed that the organization of mitochondrial cristae is altered during the mitochondrial clearance phase in differentiating primary human erythroblasts stably expressing ΔN63 Atg4D, and that these cells have elevated levels of mitochondrial reactive oxygen species (ROS) during late stages of erythropoiesis. Together these data suggest that the import of Atg4D during cellular stress and differentiation may play important roles in the regulation of mitochondrial physiology, ROS, mitophagy and cell viability.
MeSH term(s)	Amino Acid Motifs ; Amino Acid Sequence ; Autophagy ; Autophagy-Related Proteins ; Caspases/metabolism ; Cell Survival ; Cysteine Endopeptidases/chemistry ; Cysteine Endopeptidases/metabolism ; Erythroblasts/metabolism ; Erythroblasts/ultrastructure ; Green Fluorescent Proteins/metabolism ; HeLa Cells ; Humans ; Mitochondria/metabolism ; Mitochondria/ultrastructure ; Molecular Sequence Data ; Mutant Proteins/metabolism ; Oxidative Stress ; Protein Sorting Signals ; Protein Transport
Chemical Substances	Autophagy-Related Proteins ; Mutant Proteins ; Protein Sorting Signals ; Green Fluorescent Proteins (147336-22-9) ; ATG4D protein, human (EC 3.4.22.-) ; Caspases (EC 3.4.22.-) ; Cysteine Endopeptidases (EC 3.4.22.-)
Language	English
Publishing date	2012-04-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.4161/auto.19227
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