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Article: Unexpected inhibition of the lipid kinase PIKfyve reveals an epistatic role for p38 MAPKs in endolysosomal fission and volume control.

Wible, Daric J / Parikh, Zalak / Cho, Eun Jeong / Chen, Miao-Der / Mukhopadhyay, Somshuvra / Dalby, Kevin N / Varadarajan, Shankar / Bratton, Shawn B

bioRxiv : the preprint server for biology

2023

Abstract: p38 mitogen-activated protein kinases (MAPKs) regulate early endocytic trafficking, but their effects on late endocytic trafficking remain unclear. Herein, we report that the pyridinyl imidazole p38 MAPK inhibitors, SB203580 and SB202190, induce a rapid ... ...

Abstract	p38 mitogen-activated protein kinases (MAPKs) regulate early endocytic trafficking, but their effects on late endocytic trafficking remain unclear. Herein, we report that the pyridinyl imidazole p38 MAPK inhibitors, SB203580 and SB202190, induce a rapid but reversible Rab7-dependent accumulation of large cytoplasmic vacuoles. While SB203580 did not induce canonical autophagy, phosphatidylinositol 3-phosphate [PI(3)P] accumulated on vacuole membranes, and inhibition of the class III PI3-kinase (PIK3C3/VPS34) suppressed vacuolation. Ultimately, vacuolation resulted from the fusion of ER/Golgi-derived membrane vesicles with late endosomes and lysosomes (LELs), combined with an osmotic imbalance in LELs that led to severe swelling and a decrease in LEL fission. Since PIKfyve inhibitors induce a similar phenotype by preventing the conversion of PI(3)P to PI(3,5)P2, we performed
Language	English
Publishing date	2023-03-14
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.03.13.532495
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Article: Caspase-9 swings both ways in the apoptosome.

Wu, Chu-Chiao / Bratton, Shawn B

Molecular & cellular oncology

2017 Volume 4, Issue 2, Page(s) e1281865

Abstract: For nearly 2 decades, investigators have debated whether cysteinyl-aspartate-specific protease 9 (caspase-9) is activated within the apoptotic protease-activating factor 1 (Apaf-1) apoptosome through proximity-induced homodimerization or through ... ...

Abstract	For nearly 2 decades, investigators have debated whether cysteinyl-aspartate-specific protease 9 (caspase-9) is activated within the apoptotic protease-activating factor 1 (Apaf-1) apoptosome through proximity-induced homodimerization or through formation of a holoenzyme. Recently, we have demonstrated that caspase-9 forms (and likely transitions between) both caspase-9 homo- and Apaf-1:caspase-9 heterodimers, each of which plays unique roles in the recruitment and activation of caspase-9.
Language	English
Publishing date	2017-01-20
Publishing country	United States
Document type	Journal Article
ISSN	2372-3556
ISSN	2372-3556
DOI	10.1080/23723556.2017.1281865
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Article ; Online: Peptide inhibitors: Four of a kind beats a pair.

Bratton, Shawn B

Nature chemical biology

2012 Volume 8, Issue 7, Page(s) 606–607

MeSH term(s)	Biopolymers/metabolism ; Caspase 6/metabolism ; Enzyme Precursors/metabolism ; Humans ; Peptides/metabolism
Chemical Substances	Biopolymers ; Enzyme Precursors ; Peptides ; Caspase 6 (EC 3.4.22.-)
Language	English
Publishing date	2012-06-18
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2202962-X
ISSN	1552-4469 ; 1552-4450
ISSN (online)	1552-4469
ISSN	1552-4450
DOI	10.1038/nchembio.1000
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Zs.A 6251: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Unexpected inhibition of the lipid kinase PIKfyve reveals an epistatic role for p38 MAPKs in endolysosomal fission and volume control.

Wible, Daric J / Parikh, Zalak / Cho, Eun Jeong / Chen, Miao-Der / Jeter, Collene R / Mukhopadhyay, Somshuvra / Dalby, Kevin N / Varadarajan, Shankar / Bratton, Shawn B

Cell death & disease

2024 Volume 15, Issue 1, Page(s) 80

Abstract: p38 mitogen-activated protein kinases (MAPKs) participate in autophagic signaling; and previous reports suggest that pyridinyl imidazole p38 MAPK inhibitors, including SB203580 and SB202190, induce cell death in some cancer cell-types through ... ...

Abstract	p38 mitogen-activated protein kinases (MAPKs) participate in autophagic signaling; and previous reports suggest that pyridinyl imidazole p38 MAPK inhibitors, including SB203580 and SB202190, induce cell death in some cancer cell-types through unrestrained autophagy. Subsequent studies, however, have suggested that the associated cytoplasmic vacuolation resulted from off-target inhibition of an unidentified enzyme. Herein, we report that SB203580-induced vacuolation is rapid, reversible, and relies on the class III phosphatidylinositol 3-kinase (PIK3C3) complex and the production of phosphatidylinositol 3-phosphate [PI(3)P] but not on autophagy per se. Rather, vacuolation resulted from the accumulation of Rab7 on late endosome and lysosome (LEL) membranes, combined with an osmotic imbalance that triggered severe swelling in these organelles. Inhibition of PIKfyve, the lipid kinase that converts PI(3)P to PI(3,5)P2 on LEL membranes, produced a similar phenotype in cells; therefore, we performed in vitro kinase assays and discovered that both SB203580 and SB202190 directly inhibited recombinant PIKfyve. Cancer cells treated with either drug likewise displayed significant reductions in the endogenous levels of PI(3,5)P2. Despite these results, SB203580-induced vacuolation was not entirely due to off-target inhibition of PIKfyve, as a drug-resistant p38α mutant suppressed vacuolation; and combined genetic deletion of both p38α and p38β dramatically sensitized cells to established PIKfyve inhibitors, including YM201636 and apilimod. The rate of vacuole dissolution (i.e., LEL fission), following the removal of apilimod, was also significantly reduced in cells treated with BIRB-796, a structurally unrelated p38 MAPK inhibitor. Thus, our studies indicate that pyridinyl imidazole p38 MAPK inhibitors induce cytoplasmic vacuolation through the combined inhibition of both PIKfyve and p38 MAPKs, and more generally, that p38 MAPKs act epistatically to PIKfyve, most likely to promote LEL fission.
MeSH term(s)	Lysosomes ; Endosomes ; Phosphatidylinositol Phosphates ; Imidazoles/pharmacology ; Hydrazones ; Morpholines ; Pyrimidines
Chemical Substances	apilimod (GFW2K84S4L) ; phosphatidylinositol 3-phosphate ; Phosphatidylinositol Phosphates ; Imidazoles ; Hydrazones ; Morpholines ; Pyrimidines
Language	English
Publishing date	2024-01-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2541626-1
ISSN	2041-4889 ; 2041-4889
ISSN (online)	2041-4889
ISSN	2041-4889
DOI	10.1038/s41419-024-06423-0
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Article: Reciprocity in ROS and autophagic signaling.

Wible, Daric J / Bratton, Shawn B

Current opinion in toxicology

2017 Volume 7, Page(s) 28–36

Abstract: Reactive oxygen species (ROS) are important signaling molecules that mediate oxidative stress and cellular damage when improperly regulated. ROS and oxidative stress can activate autophagy, which generally serves as a cytoprotective negative feedback ... ...

Abstract	Reactive oxygen species (ROS) are important signaling molecules that mediate oxidative stress and cellular damage when improperly regulated. ROS and oxidative stress can activate autophagy, which generally serves as a cytoprotective negative feedback mechanism to selectively eliminate sources of ROS, including mitochondria and peroxisomes. In this review we describe the mechanisms by which ROS directly and indirectly activate autophagy, and conversely, how selective autophagy suppresses the formation of ROS. Furthermore, we highlight what appear to be contradictory examples in which ROS suppress, rather than activate, autophagy; and where selective autophagy promotes, rather than inhibits ROS production, thereby contributing to cell death. Given that ROS are implicated in cancer, diabetes, atherosclerosis, neurodegenerative diseases and ischemia/reperfusion injury, a deeper understanding of the connections linking ROS and autophagy is greatly needed.
Language	English
Publishing date	2017-10-12
Publishing country	Netherlands
Document type	Journal Article
ISSN	2468-2934
ISSN	2468-2934
DOI	10.1016/j.cotox.2017.10.006
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Article ; Online: DrICE resurrects Grim to antagonize DIAP1.

Yeh, Ting-Chun / Bratton, Shawn B

Cell cycle (Georgetown, Tex.)

2014 Volume 13, Issue 5, Page(s) 685–686

MeSH term(s)	Animals ; Caspases/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Ubiquitin/metabolism
Chemical Substances	Ubiquitin ; Caspases (EC 3.4.22.-) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2014-01-21
Publishing country	United States
Document type	Editorial ; Comment
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.4161/cc.27857
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Article: ATG5

Wible, Daric J / Chao, Hsueh-Ping / Tang, Dean G / Bratton, Shawn B

Cell discovery

2019 Volume 5, Page(s) 42

Abstract: Autophagy is critical for maintaining cellular homeostasis during times of stress, and is thought to play important roles in both tumorigenesis and tumor cell survival. Formation of autophagosomes, which mediate delivery of cytoplasmic cargo to lysosomes, ...

Abstract	Autophagy is critical for maintaining cellular homeostasis during times of stress, and is thought to play important roles in both tumorigenesis and tumor cell survival. Formation of autophagosomes, which mediate delivery of cytoplasmic cargo to lysosomes, requires multiple autophagy-related (ATG) protein complexes, including the ATG12-ATG5-ATG16L1 complex. Herein, we report that a molecular ATG5 "conjugation switch", comprised of competing ATG12 and ubiquitin conjugation reactions, integrates ATG12-ATG5-ATG16L1 complex assembly with protein quality control of its otherwise highly unstable subunits. This conjugation switch is tightly regulated by ATG16L1, which binds to free ATG5 and mutually protects both proteins from ubiquitin conjugation and proteasomal degradation, thereby instead promoting the irreversible conjugation of ATG12 to ATG5. The resulting ATG12-ATG5 conjugate, in turn, displays enhanced affinity for ATG16L1 and thus fully stabilizes the ATG12-ATG5-ATG16L1 complex. Most importantly, we find in multiple tumor types that ATG5 somatic mutations and alternative mRNA splicing specifically disrupt the ATG16L1-binding pocket in ATG5 and impair the essential ATG5-ATG16L1 interactions that are initially required for ATG12-ATG5 conjugation. Finally, we provide evidence that ATG16L2, which is overexpressed in several cancers relative to ATG16L1, hijacks the conjugation switch by competing with ATG16L1 for binding to ATG5. While ATG16L2 stabilizes ATG5 and enables ATG12-ATG5 conjugation, this endogenous dominant-negative inhibitor simultaneously displaces ATG16L1, resulting in its proteasomal degradation and a block in autophagy. Thus, collectively, our findings provide novel insights into ATG12-ATG5-ATG16L1 complex assembly and reveal multiple mechanisms wherein dysregulation of the ATG5 conjugation switch inhibits autophagy.
Language	English
Publishing date	2019-08-27
Publishing country	England
Document type	Journal Article
ISSN	2056-5968
ISSN	2056-5968
DOI	10.1038/s41421-019-0110-1
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Article ; Online: Caspase-dependent regulation of the ubiquitin-proteasome system through direct substrate targeting.

Yeh, Ting-Chun / Bratton, Shawn B

Proceedings of the National Academy of Sciences of the United States of America

2013 Volume 110, Issue 35, Page(s) 14284–14289

Abstract: Drosophila inhibitor of apoptosis (IAP) 1 (DIAP1) is an E3 ubiquitin ligase that regulates apoptosis in flies, in large part through direct inhibition and/or ubiquitinylation of caspases. IAP antagonists, such as Reaper, Hid, and Grim, are thought to ... ...

Abstract	Drosophila inhibitor of apoptosis (IAP) 1 (DIAP1) is an E3 ubiquitin ligase that regulates apoptosis in flies, in large part through direct inhibition and/or ubiquitinylation of caspases. IAP antagonists, such as Reaper, Hid, and Grim, are thought to induce cell death by displacing active caspases from baculovirus IAP repeat domains in DIAP1, but can themselves become targets of DIAP1-mediated ubiquitinylation. Herein, we demonstrate that Grim self-associates in cells and is ubiquitinylated by DIAP1 at Lys136 in an UbcD1-dependent manner, resulting in its rapid turnover. K48-linked ubiquitin chains are added almost exclusively to BIR2-bound Grim as a result of its structural proximity to DIAP1's RING domain. However, active caspases can simultaneously cleave Grim at Asp132, removing the lysine necessary for ubiquitinylation as well as any existing ubiquitin conjugates. Cleavage therefore enhances the stability of Grim and initiates a feed-forward caspase amplification loop, resulting in greater cell death. In summary, Grim is a caspase substrate whose cleavage promotes apoptosis by limiting, in a target-specific fashion, its ubiquitinylation and turnover by the proteasome.
MeSH term(s)	Animals ; Apoptosis ; Caspases/metabolism ; Drosophila Proteins/metabolism ; Drosophila melanogaster ; Enzyme Activation ; Inhibitor of Apoptosis Proteins/metabolism ; Neuropeptides/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Proteolysis ; Substrate Specificity ; Ubiquitin/metabolism ; Ubiquitination
Chemical Substances	DIAP1 protein, Drosophila ; Drosophila Proteins ; Inhibitor of Apoptosis Proteins ; Neuropeptides ; Ubiquitin ; grim protein, Drosophila ; Caspases (EC 3.4.22.-) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2013-08-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1306179110
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Article ; Online: Regulation of the intrinsic apoptosis pathway by reactive oxygen species.

Wu, Chu-Chiao / Bratton, Shawn B

Antioxidants & redox signaling

2012 Volume 19, Issue 6, Page(s) 546–558

Abstract: ... Recent advances: B cell lymphoma-2 (BCL-2) family members regulate cell death, primarily via ...

Abstract	Significance: The intrinsic apoptosis pathway is conserved from worms to humans and plays a critical role in the normal development and homeostatic control of adult tissues. As a result, numerous diseases from cancer to neurodegeneration are associated with either too little or too much apoptosis. Recent advances: B cell lymphoma-2 (BCL-2) family members regulate cell death, primarily via their effects on mitochondria. In stressed cells, proapoptotic BCL-2 family members promote mitochondrial outer membrane permeabilization (MOMP) and cytochrome c (cyt c) release into the cytoplasm, where it stimulates formation of the "apoptosome." This large, multimeric complex is composed of the adapter protein, apoptotic protease-activating factor-1, and the cysteine protease, caspase-9. Recent studies suggest that proteins involved in the processes leading up to (and including) formation of the apoptosome are subject to various forms of post-translational modification, including proteolysis, phosphorylation, and in some cases, direct oxidative modification. Critical issues: Despite intense investigation of the intrinsic pathway, significant questions remain regarding how cyt c is released from mitochondria, how the apoptosome is formed and regulated, and how caspase-9 is activated within the complex. Future directions: Further studies on the biochemistry of MOMP and apoptosome formation are needed to understand the mechanisms that underpin these critical processes, and novel animal models will be necessary in the future to ascertain the importance of the many posttranslational modifications reported for BCL-2 family members and components of the apoptosome.
MeSH term(s)	Animals ; Apoptosis ; Caspase 9/metabolism ; Cytochromes c/metabolism ; Humans ; Mitochondrial Membrane Transport Proteins/metabolism ; Mitochondrial Membranes ; Mitochondrial Permeability Transition Pore ; Oxidative Stress ; Permeability ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/metabolism
Chemical Substances	Mitochondrial Membrane Transport Proteins ; Mitochondrial Permeability Transition Pore ; Proto-Oncogene Proteins c-bcl-2 ; Reactive Oxygen Species ; Cytochromes c (9007-43-6) ; CASP9 protein, human (EC 3.4.22.-) ; Caspase 9 (EC 3.4.22.-)
Language	English
Publishing date	2012-10-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1483836-9
ISSN	1557-7716 ; 1523-0864
ISSN (online)	1557-7716
ISSN	1523-0864
DOI	10.1089/ars.2012.4905
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Zs.A 5488: Show issues

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Article ; Online: DARK apoptosome secrets come to light.

Wu, Chu-Chiao / Bratton, Shawn B

Structure (London, England : 1993)

2010 Volume 19, Issue 1, Page(s) 4–6

Abstract: In this issue of Structure, Yuan et al. (2011) utilize biochemical approaches to reconstitute an active Drosophila apoptosome, as well as cryo-electron microscopy to generate an improved model for this conserved caspase-activating complex. ...

Abstract	In this issue of Structure, Yuan et al. (2011) utilize biochemical approaches to reconstitute an active Drosophila apoptosome, as well as cryo-electron microscopy to generate an improved model for this conserved caspase-activating complex.
Language	English
Publishing date	2010-12-03
Publishing country	United States
Document type	Comment ; Journal Article
ZDB-ID	1213087-4
ISSN	1878-4186 ; 0969-2126
ISSN (online)	1878-4186
ISSN	0969-2126
DOI	10.1016/j.str.2010.12.009
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