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Article ; Online: CELLULAR, A Cell Autophagy Imaging Dataset.

Al Outa, Amani / Hicks, Steven / Thambawita, Vajira / Andresen, Siri / Enserink, Jorrit M / Halvorsen, Pål / Riegler, Michael A / Knævelsrud, Helene

Scientific data

2023 Volume 10, Issue 1, Page(s) 806

Abstract: Cells in living organisms are dynamic compartments that continuously respond to changes in their environment to maintain physiological homeostasis. While basal autophagy exists in cells to aid in the regular turnover of intracellular material, autophagy ... ...

Abstract	Cells in living organisms are dynamic compartments that continuously respond to changes in their environment to maintain physiological homeostasis. While basal autophagy exists in cells to aid in the regular turnover of intracellular material, autophagy is also a critical cellular response to stress, such as nutritional depletion. Conversely, the deregulation of autophagy is linked to several diseases, such as cancer, and hence, autophagy constitutes a potential therapeutic target. Image analysis to follow autophagy in cells, especially on high-content screens, has proven to be a bottleneck. Machine learning (ML) algorithms have recently emerged as crucial in analyzing images to efficiently extract information, thus contributing to a better understanding of the questions at hand. This paper presents CELLULAR, an open dataset consisting of images of cells expressing the autophagy reporter mRFP-EGFP-Atg8a with cell-specific segmentation masks. Each cell is annotated into either basal autophagy, activated autophagy, or unknown. Furthermore, we introduce some preliminary experiments using the dataset that can be used as a baseline for future research.
MeSH term(s)	Autophagy/physiology ; Humans ; Animals
Language	English
Publishing date	2023-11-16
Publishing country	England
Document type	Dataset ; Journal Article
ZDB-ID	2775191-0
ISSN	2052-4463 ; 2052-4463
ISSN (online)	2052-4463
ISSN	2052-4463
DOI	10.1038/s41597-023-02687-x
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Article ; Online: The human leukemic oncogene MLL-AF4 promotes hyperplastic growth of hematopoietic tissues in

Johannessen, Julie A / Formica, Miriam / Haukeland, Aina Louise C / Bråthen, Nora Rojahn / Al Outa, Amani / Aarsund, Miriam / Therrien, Marc / Enserink, Jorrit M / Knævelsrud, Helene

iScience

2023 Volume 26, Issue 10, Page(s) 107726

Abstract: ... ...

Abstract	MLL
Language	English
Publishing date	2023-08-25
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2023.107726
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Article ; Online: HS1BP3 inhibits autophagy by regulation of PLD1.

Søreng, Kristiane / Knævelsrud, Helene / Holland, Petter / Simonsen, Anne

Autophagy

2017 Volume 13, Issue 5, Page(s) 985–986

Abstract: Macroautophagy/autophagy is a membrane trafficking and intracellular degradation process involving the formation of double-membrane autophagosomes and their ultimate fusion with lysosomes. Much is yet to be learned about the regulation of this process, ... ...

Abstract	Macroautophagy/autophagy is a membrane trafficking and intracellular degradation process involving the formation of double-membrane autophagosomes and their ultimate fusion with lysosomes. Much is yet to be learned about the regulation of this process, especially at the level of the membranes and lipids involved. We have recently found that the PX domain protein HS1BP3 (HCLS1 binding protein 3) is a negative regulator of autophagosome formation. HS1BP3 depletion increases the formation of LC3-positive autophagosomes both in human cells and zebrafish. HS1BP3 localizes to ATG16L1- and ATG9-positive autophagosome precursors deriving from recycling endosomes, which appear to fuse with LC3-positive phagophores. The HS1BP3 PX domain interacts with phosphatidic acid (PA) and 3'-phosphorylated phosphoinositides. When HS1BP3 is depleted, the total cellular PA content is upregulated stemming from increased activity of the PA-producing enzyme PLD (phospholipase D) and increased localization of PLD1 to ATG16L1-positive membranes. We propose that HS1BP3 negatively regulates autophagy by decreasing the PA content of the ATG16L1-positive autophagosome precursor membranes through inhibition of PLD1 activity and localization.
Language	English
Publishing date	2017-05-04
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	10.1080/15548627.2017.1291483
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Article ; Online: V-ATPase controls tumor growth and autophagy in a Drosophila model of gliomagenesis.

Formica, Miriam / Storaci, Alessandra Maria / Bertolini, Irene / Carminati, Francesca / Knævelsrud, Helene / Vaira, Valentina / Vaccari, Thomas

Autophagy

2021 Volume 17, Issue 12, Page(s) 4442–4452

Abstract: Glioblastoma (GBM), a very aggressive and incurable tumor, often results from constitutive activation of EGFR (epidermal growth factor receptor) and of phosphoinositide 3-kinase (PI3K). To understand the role of autophagy in the pathogenesis of glial ... ...

Abstract	Glioblastoma (GBM), a very aggressive and incurable tumor, often results from constitutive activation of EGFR (epidermal growth factor receptor) and of phosphoinositide 3-kinase (PI3K). To understand the role of autophagy in the pathogenesis of glial tumors
MeSH term(s)	Animals ; Autophagy/genetics ; Drosophila/metabolism ; Drosophila melanogaster/metabolism ; Humans ; Lysosomes/metabolism ; Neoplasms/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Vacuolar Proton-Translocating ATPases/metabolism
Chemical Substances	Vacuolar Proton-Translocating ATPases (EC 3.6.1.-)
Language	English
Publishing date	2021-05-12
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	10.1080/15548627.2021.1918915
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Article: Lipids in autophagy: constituents, signaling molecules and cargo with relevance to disease.

Knævelsrud, Helene / Simonsen, Anne

Biochimica et biophysica acta

2012 Volume 1821, Issue 8, Page(s) 1133–1145

Abstract: The balance between protein and lipid biosynthesis and their eventual degradation is a critical component of cellular health. Autophagy, the catabolic process by which cytoplasmic material becomes degraded in lysosomes, can be induced by various ... ...

Abstract	The balance between protein and lipid biosynthesis and their eventual degradation is a critical component of cellular health. Autophagy, the catabolic process by which cytoplasmic material becomes degraded in lysosomes, can be induced by various physiological stimuli to maintain cellular homeostasis. Autophagy was for a long time considered a non-selective bulk process, but recent data have shown that unwanted components such as aberrant protein aggregates, dysfunctional organelles and invading pathogens can be selectively eliminated by autophagy. Recently, also intracellular lipid droplets were described as specific autophagic cargo, indicating that autophagy plays a role in lipid metabolism and storage (Singh et al., 2009 [1]). Moreover, over the past several years, it has become increasingly evident that lipids and lipid-modifying enzymes play important roles in the autophagy process itself, both at the level of regulation of autophagy and as membrane constituents required for formation of autophagic vesicles. In this review, we will discuss the interplay between lipids and autophagy, as well as the role of lipid-binding proteins in autophagy. We also comment on the possible implications of this mutual interaction in the context of disease. This article is part of a Special Issue entitled Lipids and Vesicular Transport.
MeSH term(s)	Animals ; Autophagy ; Cytoplasm/metabolism ; Fatty Acid-Binding Proteins/deficiency ; Fatty Acid-Binding Proteins/genetics ; Gene Expression ; Humans ; Lipid Metabolism ; Lipid Metabolism Disorders/metabolism ; Lysosomes/metabolism ; Phagosomes/metabolism ; Signal Transduction
Chemical Substances	Fatty Acid-Binding Proteins
Language	English
Publishing date	2012-08
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbalip.2012.01.001
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Article ; Online: Fighting disease by selective autophagy of aggregate-prone proteins.

Knaevelsrud, Helene / Simonsen, Anne

FEBS letters

2010 Volume 584, Issue 12, Page(s) 2635–2645

Abstract: Ubiquitinated protein aggregates are hallmarks of a range of human diseases, including neurodegenerative, liver and muscle disorders. These protein aggregates are typically positive for the autophagy receptor p62. Whereas the ubiquitin-proteasome system ( ...

Abstract	Ubiquitinated protein aggregates are hallmarks of a range of human diseases, including neurodegenerative, liver and muscle disorders. These protein aggregates are typically positive for the autophagy receptor p62. Whereas the ubiquitin-proteasome system (UPS) degrades shortlived and misfolded ubiquitinated proteins that are small enough to enter the narrow pore of the barrel-shaped proteasome, the lysosomal pathway of autophagy can degrade larger structures including entire organelles or protein aggregates. This degradation requires autophagy receptors that link the cargo with the molecular machinery of autophagy and is enhanced by certain posttranslational modifications of the cargo. In this review we focus on how autophagy clears aggregate-prone proteins and the relevance of this process to protein aggregate associated diseases.
MeSH term(s)	Acetylation ; Active Transport, Cell Nucleus ; Adaptor Proteins, Signal Transducing/chemistry ; Adaptor Proteins, Signal Transducing/metabolism ; Autophagy/physiology ; Histone Deacetylase 6 ; Histone Deacetylases/chemistry ; Histone Deacetylases/metabolism ; Humans ; Membrane Proteins/chemistry ; Membrane Proteins/metabolism ; Models, Biological ; Multiprotein Complexes/chemistry ; Multiprotein Complexes/metabolism ; Neurodegenerative Diseases/etiology ; Neurodegenerative Diseases/metabolism ; Neurodegenerative Diseases/therapy ; Phosphorylation ; Proteasome Endopeptidase Complex/metabolism ; Protein Transport ; Proteins/chemistry ; Proteins/metabolism ; Sequestosome-1 Protein ; Transcription Factors/chemistry ; Transcription Factors/metabolism ; Ubiquitinated Proteins/chemistry ; Ubiquitinated Proteins/metabolism ; Ubiquitination ; Unfolded Protein Response
Chemical Substances	Adaptor Proteins, Signal Transducing ; Membrane Proteins ; Multiprotein Complexes ; NBR1 protein, human ; Proteins ; SQSTM1 protein, human ; Sequestosome-1 Protein ; Transcription Factors ; Ubiquitinated Proteins ; WDFY3 protein, human ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; HDAC6 protein, human (EC 3.5.1.98) ; Histone Deacetylase 6 (EC 3.5.1.98) ; Histone Deacetylases (EC 3.5.1.98)
Language	English
Publishing date	2010-06-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	212746-5
ISSN	1873-3468 ; 0014-5793
ISSN (online)	1873-3468
ISSN	0014-5793
DOI	10.1016/j.febslet.2010.04.041
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Article ; Online: SNX18 tubulates recycling endosomes for autophagosome biogenesis.

Knævelsrud, Helene / Carlsson, Sven R / Simonsen, Anne

Autophagy

2013 Volume 9, Issue 10, Page(s) 1639–1641

Abstract: The role of membrane remodeling and phosphoinositide-binding proteins in autophagy remains elusive. PX domain proteins bind phosphoinositides and participate in membrane remodeling and trafficking events and we therefore hypothesized that one or several ... ...

Abstract	The role of membrane remodeling and phosphoinositide-binding proteins in autophagy remains elusive. PX domain proteins bind phosphoinositides and participate in membrane remodeling and trafficking events and we therefore hypothesized that one or several PX domain proteins are involved in autophagy. Indeed, the PX-BAR protein SNX18 was identified as a positive regulator of autophagosome formation using an image-based siRNA screen. We show that SNX18 interacts with ATG16L1 and LC3, and functions downstream of ATG14 and the class III PtdIns3K complex in autophagosome formation. SNX18 facilitates recruitment of ATG16L1 to perinuclear recycling endosomes, and its overexpression leads to tubulation of ATG16L1- and LC3-positive membranes. We propose that SNX18 promotes LC3 lipidation and tubulation of recycling endosomes to provide membrane for phagophore expansion.
MeSH term(s)	Animals ; Autophagy/genetics ; Autophagy/physiology ; Carrier Proteins/metabolism ; Cell Membrane/metabolism ; Endosomes/metabolism ; Humans ; Phagosomes/metabolism ; Sorting Nexins/metabolism
Chemical Substances	Carrier Proteins ; SNX18 protein, human ; Sorting Nexins
Language	English
Publishing date	2013-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.4161/auto.26124
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Article ; Online: Apical accumulation of the Sevenless receptor tyrosine kinase during Drosophila eye development is promoted by the small GTPase Rap1.

Baril, Caroline / Lefrançois, Martin / Sahmi, Malha / Knævelsrud, Helene / Therrien, Marc

Genetics

2014 Volume 197, Issue 4, Page(s) 1237–1250

Abstract: The Ras/MAPK-signaling pathway plays pivotal roles during development of metazoans by controlling cell proliferation and cell differentiation elicited, in several instances, by receptor tyrosine kinases (RTKs). While the internal mechanism of RTK-driven ... ...

Abstract	The Ras/MAPK-signaling pathway plays pivotal roles during development of metazoans by controlling cell proliferation and cell differentiation elicited, in several instances, by receptor tyrosine kinases (RTKs). While the internal mechanism of RTK-driven Ras/MAPK signaling is well understood, far less is known regarding its interplay with other co-required signaling events involved in developmental decisions. In a genetic screen designed to identify new regulators of RTK/Ras/MAPK signaling during Drosophila eye development, we identified the small GTPase Rap1, PDZ-GEF, and Canoe as components contributing to Ras/MAPK-mediated R7 cell differentiation. Rap1 signaling has recently been found to participate in assembling cadherin-based adherens junctions in various fly epithelial tissues. Here, we show that Rap1 activity is required for the integrity of the apical domains of developing photoreceptor cells and that reduced Rap1 signaling hampers the apical accumulation of the Sevenless RTK in presumptive R7 cells. It thus appears that, in addition to its role in cell-cell adhesion, Rap1 signaling controls the partitioning of the epithelial cell membrane, which in turn influences signaling events that rely on apico-basal cell polarity.
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Adherens Junctions/genetics ; Adherens Junctions/metabolism ; Animals ; Cell Adhesion/genetics ; Cell Differentiation/genetics ; Cell Polarity/genetics ; Chromosome Mapping ; Drosophila/embryology ; Drosophila/genetics ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Epithelial Cells/metabolism ; Eye/embryology ; Eye Proteins/genetics ; Eye Proteins/metabolism ; Gene Expression Regulation, Developmental ; MAP Kinase Signaling System ; Organogenesis/genetics ; Photoreceptor Cells, Invertebrate/metabolism ; Receptor Protein-Tyrosine Kinases/genetics ; Receptor Protein-Tyrosine Kinases/metabolism ; rap1 GTP-Binding Proteins/genetics ; rap1 GTP-Binding Proteins/metabolism
Chemical Substances	Adaptor Proteins, Signal Transducing ; CNK protein, Drosophila ; Drosophila Proteins ; Eye Proteins ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; sev protein, Drosophila (EC 2.7.10.1) ; rap1 GTP-Binding Proteins (EC 3.6.5.2)
Language	English
Publishing date	2014-06-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2167-2
ISSN	1943-2631 ; 0016-6731
ISSN (online)	1943-2631
ISSN	0016-6731
DOI	10.1534/genetics.114.166272
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Article ; Online: Human NUP98-HOXA9 promotes hyperplastic growth of hematopoietic tissues in Drosophila.

Baril, Caroline / Gavory, Gwenaëlle / Bidla, Gawa / Knævelsrud, Helene / Sauvageau, Guy / Therrien, Marc

Developmental biology

2016 Volume 421, Issue 1, Page(s) 16–26

Abstract: Acute myeloid leukemia (AML) is a complex malignancy with poor prognosis. Several genetic lesions can lead to the disease. One of these corresponds to the NUP98-HOXA9 (NA9) translocation that fuses sequences encoding the N-terminal part of NUP98 to those ...

Abstract	Acute myeloid leukemia (AML) is a complex malignancy with poor prognosis. Several genetic lesions can lead to the disease. One of these corresponds to the NUP98-HOXA9 (NA9) translocation that fuses sequences encoding the N-terminal part of NUP98 to those encoding the DNA-binding domain of HOXA9. Despite several studies, the mechanism underlying NA9 ability to induce leukemia is still unclear. To bridge this gap, we sought to functionally dissect NA9 activity using Drosophila. For this, we generated transgenic NA9 fly lines and expressed the oncoprotein during larval hematopoiesis. This markedly enhanced cell proliferation and tissue growth, but did not alter cell fate specification. Moreover, reminiscent to NA9 activity in mammals, strong cooperation was observed between NA9 and the MEIS homolog HTH. Genetic characterization of NA9-induced phenotypes suggested interference with PVR (Flt1-4 RTK homolog) signaling, which is similar to functional interactions observed in mammals between Flt3 and HOXA9 in leukemia. Finally, NA9 expression was also found to induce non-cell autonomous effects, raising the possibility that its leukemia-inducing activity also relies on this property. Together, our work suggests that NA9 ability to induce blood cell expansion is evolutionarily conserved. The amenability of NA9 activity to a genetically-tractable system should facilitate unraveling its molecular underpinnings.
MeSH term(s)	Animals ; Cell Differentiation ; Cell Proliferation ; Drosophila Proteins/metabolism ; Drosophila melanogaster/growth & development ; Drosophila melanogaster/metabolism ; Hematopoiesis ; Hemocytes/pathology ; Homeodomain Proteins/metabolism ; Humans ; Hyperplasia ; Lymphoid Tissue/growth & development ; Lymphoid Tissue/pathology ; Mammals ; Mitotic Index ; Nuclear Pore Complex Proteins/metabolism ; Phenotype ; Receptor Protein-Tyrosine Kinases/metabolism ; Signal Transduction ; Stem Cells/cytology
Chemical Substances	Drosophila Proteins ; Homeodomain Proteins ; Nuclear Pore Complex Proteins ; homeobox protein HOXA9 ; hth protein, Drosophila ; nuclear pore complex protein 98 ; Pvr protein, Drosophila (EC 2.7.10.1) ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1)
Language	English
Publishing date	2016-11-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	1114-9
ISSN	1095-564X ; 0012-1606
ISSN (online)	1095-564X
ISSN	0012-1606
DOI	10.1016/j.ydbio.2016.11.003
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Article ; Online: The N-terminal Region of the Ubiquitin Regulatory X (UBX) Domain-containing Protein 1 (UBXD1) Modulates Interdomain Communication within the Valosin-containing Protein p97.

Trusch, Franziska / Matena, Anja / Vuk, Maja / Koerver, Lisa / Knævelsrud, Helene / Freemont, Paul S / Meyer, Hemmo / Bayer, Peter

The Journal of biological chemistry

2015 Volume 290, Issue 49, Page(s) 29414–29427

Abstract: Valosin-containing protein/p97 is an ATP-driven protein segregase that cooperates with distinct protein cofactors to control various aspects of cellular homeostasis. Mutations at the interface between the regulatory N-domain and the first of two ATPase ... ...

Abstract	Valosin-containing protein/p97 is an ATP-driven protein segregase that cooperates with distinct protein cofactors to control various aspects of cellular homeostasis. Mutations at the interface between the regulatory N-domain and the first of two ATPase domains (D1 and D2) deregulate the ATPase activity and cause a multisystem degenerative disorder, inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia/amyotrophic lateral sclerosis. Intriguingly, the mutations affect only a subset of p97-mediated pathways correlating with unbalanced cofactor interactions and most prominently compromised binding of the ubiquitin regulatory X domain-containing protein 1 (UBXD1) cofactor during endolysosomal sorting of caveolin-1. However, how the mutations impinge on the p97-cofactor interplay is unclear so far. In cell-based endosomal localization studies, we identified a critical role of the N-terminal region of UBXD1 (UBXD1-N). Biophysical studies using NMR and CD spectroscopy revealed that UBXD1-N can be classified as intrinsically disordered. NMR titration experiments confirmed a valosin-containing protein/p97 interaction motif and identified a second binding site at helices 1 and 2 of UBXD1-N as binding interfaces for p97. In reverse titration experiments, we identified two distant epitopes on the p97 N-domain that include disease-associated residues and an additional interaction between UBXD1-N and the D1D2 barrel of p97 that was confirmed by fluorescence anisotropy. Functionally, binding of UBXD1-N to p97 led to a reduction of ATPase activity and partial protection from proteolysis. These findings indicate that UBXD1-N intercalates into the p97-ND1 interface, thereby modulating interdomain communication of p97 domains and its activity with relevance for disease pathogenesis. We propose that the polyvalent binding mode characterized for UBXD1-N is a more general principle that defines a subset of p97 cofactors.
MeSH term(s)	Adaptor Proteins, Signal Transducing ; Adaptor Proteins, Vesicular Transport ; Adenosine Triphosphatases/metabolism ; Amino Acid Motifs ; Autophagy-Related Proteins ; Binding Sites ; Carrier Proteins/chemistry ; Carrier Proteins/metabolism ; Caveolin 1/metabolism ; Cell Cycle Proteins/metabolism ; Cell Line ; Circular Dichroism ; Endosomes/metabolism ; Epitopes/chemistry ; Fluorescence Polarization ; Green Fluorescent Proteins/metabolism ; Homeostasis ; Humans ; Lysosomes/metabolism ; Magnetic Resonance Spectroscopy ; Mutation ; Nuclear Proteins/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Ubiquitin/chemistry ; Valosin Containing Protein
Chemical Substances	Adaptor Proteins, Signal Transducing ; Adaptor Proteins, Vesicular Transport ; Autophagy-Related Proteins ; Carrier Proteins ; Caveolin 1 ; Cell Cycle Proteins ; Epitopes ; Nuclear Proteins ; UBXN6 protein, human ; Ubiquitin ; Green Fluorescent Proteins (147336-22-9) ; Adenosine Triphosphatases (EC 3.6.1.-) ; VCP protein, human (EC 3.6.4.6) ; Valosin Containing Protein (EC 3.6.4.6)
Language	English
Publishing date	2015-10-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M115.680686
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