scholarly journals A pyro-phosphodegron controls MYC polyubiquitination to regulate cell survival

2020 ◽  
Author(s):  
Padmavathi Lolla ◽  
Akruti Shah ◽  
C.P. Unnikannan ◽  
Vineesha Oddi ◽  
Rashna Bhandari
Keyword(s):  
Cell Survival ◽  
Posttranslational Modification ◽  
High Energy ◽  
Growth Stress ◽  
Environmental Cues ◽  
Dependent Manner ◽  
Inositol Pyrophosphate ◽  
Inositol Pyrophosphates ◽  
Survival And Growth ◽  
Insight Into

ABSTRACTThe transcription factor MYC regulates cell survival and growth, and its level is tightly controlled in normal cells. Here, we report that serine pyrophosphorylation – an enigmatic posttranslational modification triggered by inositol pyrophosphate signaling molecules – controls MYC levels via regulated protein degradation. We find that endogenous MYC is stabilized and less polyubiquitinated in cells with reduced inositol pyrophosphates. We show that the inositol pyrophosphate 5-IP7 transfers its high-energy beta phosphate moiety to pre-phosphorylated serine residues in the central PEST domain of MYC. Pyrophosphorylation of MYC promotes its interaction with the E3 ubiquitin ligase FBW7, thereby enhancing MYC polyubiquitination and degradation. FBW7 can bind directly to the PEST domain of MYC in a pyrophosphorylation-dependent manner. A stabilized, pyrophosphorylation-deficient form of MYC increases cell death during growth stress in untransformed cells, and promotes cell proliferation in response to mitogens. Thus, control of MYC stability through a novel pyro-phosphodegron provides unexpected insight into the regulation of cell survival in response to environmental cues.

scholarly journals Inositol pyrophosphates promote MYC polyubiquitination by FBW7 to regulate cell survival

2021 ◽  
Author(s):  
Padmavathi Lolla ◽  
Akruti Shah ◽  
Unnikannan C.P. ◽  
Vineesha Oddi ◽  
Rashna Bhandari
Keyword(s):  
Cell Survival ◽  
High Energy ◽  
Growth Stress ◽  
Environmental Cues ◽  
Wild Type ◽  
Inositol Pyrophosphate ◽  
Inositol Pyrophosphates ◽  
Survival And Growth ◽  
The Stability ◽  
Insight Into

The transcription factor MYC regulates cell survival and growth, and its level is tightly controlled in normal cells. We report that serine pyrophosphorylation – a posttranslational modification triggered by inositol pyrophosphate signaling molecules – controls MYC levels via regulated protein degradation. We find that endogenous MYC is stabilized and less polyubiquitinated in cells with reduced inositol pyrophosphates. We show that the inositol pyrophosphate 5-IP7 transfers its high-energy beta phosphate moiety to pre-phosphorylated serine residues in the central PEST domain of MYC. Loss of serine pyrophosphorylation in the PEST domain lowers the extent of MYC polyubiquitination and increases its stability. Fusion to the MYC PEST domain lowers the stability of GFP, but this effect is dependent on the extent of PEST domain pyrophosphorylation. The E3 ubiquitin ligase FBW7 can bind directly to the PEST domain of MYC, and this interaction is exclusively dependent on serine pyrophosphorylation. A stabilized, pyrophosphorylation-deficient form of MYC increases cell death during growth stress in untransformed cells. Splenocytes from mice lacking IP6K1, a kinase responsible for the synthesis of 5-IP7, have higher levels of MYC, and show increased cell proliferation in response to mitogens, compared with splenocytes from wild type mice. Thus, control of MYC stability through a novel pyro-phosphodegron provides unexpected insight into the regulation of cell survival in response to environmental cues.

Inositol pyrophosphates: between signalling and metabolism

2013 ◽  
Vol 452 (3) ◽  
pp. 369-379 ◽  
Author(s):  
Miranda S. C. Wilson ◽  
Thomas M. Livermore ◽  
Adolfo Saiardi
Keyword(s):  
High Energy ◽  
Present Review ◽  
Cellular Functions ◽  
Yeast Saccharomyces Cerevisiae ◽  
Diverse Range ◽  
Inositol Pyrophosphate ◽  
Atp Production ◽  
Recent Innovation ◽  
The Social ◽  
Inositol Pyrophosphates

The present review will explore the insights gained into inositol pyrophosphates in the 20 years since their discovery in 1993. These molecules are defined by the presence of the characteristic ‘high energy’ pyrophosphate moiety and can be found ubiquitously in eukaryotic cells. The enzymes that synthesize them are similarly well distributed and can be found encoded in any eukaryote genome. Rapid progress has been made in characterizing inositol pyrophosphate metabolism and they have been linked to a surprisingly diverse range of cellular functions. Two decades of work is now beginning to present a view of inositol pyrophosphates as fundamental, conserved and highly important agents in the regulation of cellular homoeostasis. In particular it is emerging that energy metabolism, and thus ATP production, is closely regulated by these molecules. Much of the early work on these molecules was performed in the yeast Saccharomyces cerevisiae and the social amoeba Dictyostelium discoideum, but the development of mouse knockouts for IP6K1 and IP6K2 [IP6K is IP6 (inositol hexakisphosphate) kinase] in the last 5 years has provided very welcome tools to better understand the physiological roles of inositol pyrophosphates. Another recent innovation has been the use of gel electrophoresis to detect and purify inositol pyrophosphates. Despite the advances that have been made, many aspects of inositol pyrophosphate biology remain far from clear. By evaluating the literature, the present review hopes to promote further research in this absorbing area of biology.

scholarly journals An ATP-responsive metabolic cassette comprised of inositol tris/tetrakisphosphate kinase 1 (ITPK1) and inositol pentakisphosphate 2-kinase (IPK1) buffers diphosphosphoinositol phosphate levels

2020 ◽  
Vol 477 (14) ◽  
pp. 2621-2638 ◽  
Author(s):  
Hayley Whitfield ◽  
Gaye White ◽  
Colleen Sprigg ◽  
Andrew M. Riley ◽  
Barry V.L. Potter ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Inositol Phosphate ◽  
High Energy ◽  
Dependent Manner ◽  
Inositol Polyphosphate ◽  
Inositol Polyphosphates ◽  
Inositol Pyrophosphate ◽  
Relative Contribution ◽  
Chromatographic Resolution ◽  
Molecular Signals

Inositol polyphosphates are ubiquitous molecular signals in metazoans, as are their pyrophosphorylated derivatives that bear a so-called ‘high-energy’ phosphoanhydride bond. A structural rationale is provided for the ability of Arabidopsis inositol tris/tetrakisphosphate kinase 1 to discriminate between symmetric and enantiomeric substrates in the production of diverse symmetric and asymmetric myo-inositol phosphate and diphospho-myo-inositol phosphate (inositol pyrophosphate) products. Simple tools are applied to chromatographic resolution and detection of known and novel diphosphoinositol phosphates without resort to radiolabeling approaches. It is shown that inositol tris/tetrakisphosphate kinase 1 and inositol pentakisphosphate 2-kinase comprise a reversible metabolic cassette converting Ins(3,4,5,6)P4 into 5-InsP7 and back in a nucleotide-dependent manner. Thus, inositol tris/tetrakisphosphate kinase 1 is a nexus of bioenergetics status and inositol polyphosphate/diphosphoinositol phosphate metabolism. As such, it commands a role in plants that evolution has assigned to a different class of enzyme in mammalian cells. The findings and the methods described will enable a full appraisal of the role of diphosphoinositol phosphates in plants and particularly the relative contribution of reversible inositol phosphate hydroxykinase and inositol phosphate phosphokinase activities to plant physiology.

scholarly journals The ARF tumor suppressor targets PPM1G/PP2Cγ to counteract NF-κB transcription tuning cell survival and the inflammatory response

2020 ◽  
Vol 117 (51) ◽  
pp. 32594-32605
Author(s):  
Usman Hyder ◽  
Jennifer L. McCann ◽  
Jinli Wang ◽  
Victor Fung ◽  
Juan Bayo ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cell Survival ◽  
Cell Fate ◽  
Target Gene ◽  
Environmental Cues ◽  
Dependent Manner ◽  
Gene Promoters ◽  
Induced Apoptosis ◽  
Factor Α ◽  
Necrosis Factor

Inducible transcriptional programs mediate the regulation of key biological processes and organismal functions. Despite their complexity, cells have evolved mechanisms to precisely control gene programs in response to environmental cues to regulate cell fate and maintain normal homeostasis. Upon stimulation with proinflammatory cytokines such as tumor necrosis factor-α (TNF), the master transcriptional regulator nuclear factor (NF)-κB utilizes the PPM1G/PP2Cγ phosphatase as a coactivator to normally induce inflammatory and cell survival programs. However, how PPM1G activity is precisely regulated to control NF-κB transcription magnitude and kinetics remains unknown. Here, we describe a mechanism by which the ARF tumor suppressor binds PPM1G to negatively regulate its coactivator function in the NF-κB circuit thereby promoting insult resolution. ARF becomes stabilized upon binding to PPM1G and forms a ternary protein complex with PPM1G and NF-κB at target gene promoters in a stimuli-dependent manner to provide tunable control of the NF-κB transcriptional program. Consistently, loss of ARF in colon epithelial cells leads to up-regulation of NF-κB antiapoptotic genes upon TNF stimulation and renders cells partially resistant to TNF-induced apoptosis in the presence of agents blocking the antiapoptotic program. Notably, patient tumor data analysis validates these findings by revealing that loss ofARFstrongly correlates with sustained expression of inflammatory and cell survival programs. Collectively, we propose that PPM1G emerges as a therapeutic target in a variety of cancers arising from ARF epigenetic silencing, to loss of ARF function, as well as tumors bearing oncogenic NF-κB activation.

scholarly journals Inositol Trisphosphate Kinase and Diphosphoinositol Pentakisphosphate Kinase Enzymes Constitute the Inositol Pyrophosphate Synthesis Pathway in Plants

2019 ◽  
Author(s):  
Olusegun Adepoju ◽  
Sarah P. Williams ◽  
Branch Craige ◽  
Caitlin A. Cridland ◽  
Amanda K. Sharpe ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
High Energy ◽  
Signaling Molecules ◽  
Loss Of Function ◽  
Inositol Pyrophosphate ◽  
Overexpression Line ◽  
Inositol Pyrophosphates ◽  
Intracellular Signaling Molecules ◽  
Inositol Ring

ABSTRACTInositol pyrophosphates (PP-InsPs) are an emerging class of “high-energy” intracellular signaling molecules containing one or two diphosphate groups attached to an inositol ring, with suggested roles in bioenergetic homeostasis and inorganic phosphate (Pi) sensing. Information regarding the biosynthesis of these unique class of signaling molecules in plants is scarce, however the enzymes responsible for their biosynthesis in other eukaryotes have been well described. Here we report the characterization of the two Arabidopsis VIP kinase domains, a newly discovered activity of the Arabidopsis ITPK1 and ITPK2 enzymes, and the subcellular localization of the enzymes involved in the synthesis of InsP6and PP-InsPs. Our data indicate that AtVIP1-KD and AtVIP2-KD act primarily as 1PP-specific Diphosphoinositol Pentakisphosphate Kinases (PPIP5) Kinases. The AtITPK enzymes, in contrast, can function as InsP6kinases, and thus are the missing enzyme in the plant PP-InsP synthesis pathway. Together, these enzyme classes can function in plants to produce PP-InsPs, which have been implicated in signal transduction and Pisensing pathways. We measured a higher InsP7level (increased InsP7/InsP8ratio) invip1/vip2double loss-of-function mutants, and an accumulation of InsP8(decreased InsP7/InsP8ratio) in the 35S:VIP2overexpression line relative to wild-type plants. We also report that enzymes involved in the synthesis of InsPs and PP-InsPs accumulate within the nucleus and cytoplasm of plant cells. Our work defines a molecular basis for understanding how plants synthesize PP-InsPs which is crucial for determining the roles of these signaling molecules in processes such as Pisensing.SIGNIFICANCE STATEMENTInositol pyrophosphate signaling molecules are of agronomic importance as they can control complex responses to the limited nutrient, phosphate. This work fills in the missing steps in the inositol pyrophosphate synthesis pathway and points to a role for these molecules in the plant cell nucleus. This is an important advance that can help us design future strategies to increase phosphate efficiency in plants.

DYRK1a mediates BAFF-induced noncanonical NF-kB activation to promote autoimmunity and B cell leukemogenesis

Blood ◽  
2021 ◽  
Author(s):  
Yanchuan Li ◽  
Xiaoping Xie ◽  
Zuliang Jie ◽  
Lele Zhu ◽  
Jin-Young Yang ◽  
...  
Keyword(s):  
Mouse Model ◽  
B Cell ◽  
Cell Survival ◽  
Ubiquitin Ligase ◽  
Lymphoblastic Leukemia ◽  
Dependent Manner ◽  
B Cell Activating Factor ◽  
B Cell Survival ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Insight Into

B cell-activating factor (BAFF) mediates B cell survival and, when deregulated, also contributes to autoimmune diseases and B cell malignancies. The mechanism connecting BAFF receptor (BAFFR) signal to downstream pathways and pathophysiological functions is not well understood. Here we identified DYRK1a as a kinase that responds to BAFF stimulation and mediates BAFF-induced B cell survival. B cell-specific DYRK1a deficiency causes peripheral B cell reduction and ameliorates autoimmunity in a mouse model of lupus. An unbiased screen identified DYRK1a as a protein that interacts with TRAF3, a ubiquitin ligase component mediating degradation of the noncanonical NF-kB-inducing kinase (NIK). DYRK1a phosphorylates TRAF3 at serine-29 to interfere with its function in mediating NIK degradation, thereby facilitating BAFF-induced NIK accumulation and noncanonical NF-kB activation. Interestingly, B cell acute lymphoblastic leukemia (B-ALL) cells express high levels of BAFFR and respond to BAFF for noncanonical NF-kB activation and survival in a DYRK1a-dependent manner. Furthermore, DYRK1a promotes a mouse model of B-ALL through activation of the noncanonical NF-kB pathway. These results establish DYRK1a as a critical BAFFR signaling mediator and provide novel insight into B-ALL pathogenesis.

scholarly journals Crosstalk of the Caspase Family and Mammalian Target of Rapamycin Signaling

2021 ◽  
Vol 22 (2) ◽  
pp. 817
Author(s):  
Junfang Yan ◽  
Yi Xie ◽  
Jing Si ◽  
Lu Gan ◽  
Hongyan Li ◽  
...  
Keyword(s):  
Cell Growth ◽  
Cell Survival ◽  
Cell Fate ◽  
Cellular Stress ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Signaling ◽  
Target Of Rapamycin ◽  
Dependent Manner ◽  
Caspase Family ◽  
Mediate Cell

Cell can integrate the caspase family and mammalian target of rapamycin (mTOR) signaling in response to cellular stress triggered by environment. It is necessary here to elucidate the direct response and interaction mechanism between the two signaling pathways in regulating cell survival and determining cell fate under cellular stress. Members of the caspase family are crucial regulators of inflammation, endoplasmic reticulum stress response and apoptosis. mTOR signaling is known to mediate cell growth, nutrition and metabolism. For instance, over-nutrition can cause the hyperactivation of mTOR signaling, which is associated with diabetes. Nutrition deprivation can inhibit mTOR signaling via SH3 domain-binding protein 4. It is striking that Ras GTPase-activating protein 1 is found to mediate cell survival in a caspase-dependent manner against increasing cellular stress, which describes a new model of apoptosis. The components of mTOR signaling-raptor can be cleaved by caspases to control cell growth. In addition, mTOR is identified to coordinate the defense process of the immune system by suppressing the vitality of caspase-1 or regulating other interferon regulatory factors. The present review discusses the roles of the caspase family or mTOR pathway against cellular stress and generalizes their interplay mechanism in cell fate determination.

scholarly journals Exploring Flaring Behaviour on Low Mass Stars, Solar-type Stars and the Sun

2019 ◽  
Vol 15 (S354) ◽  
pp. 384-391
Author(s):  
L. Doyle ◽  
G. Ramsay ◽  
J. G. Doyle ◽  
P. F. Wyper ◽  
E. Scullion ◽  
...  
Keyword(s):  
High Energy ◽  
The Sun ◽  
Low Mass Stars ◽  
Highly Active ◽  
Rotation Phase ◽  
Solar Type ◽  
Low Mass ◽  
Insight Into ◽  
Reconnection Model ◽  
High Cadence

AbstractWe report on our project to study the activity in both the Sun and low mass stars. Utilising high cadence, Hα observations of a filament eruption made using the CRISP spectropolarimeter mounted on the Swedish Solar Telescope has allowed us to determine 3D velocity maps of the event. To gain insight into the physical mechanism which drives the event we have qualitatively compared our observation to a 3D MHD reconnection model. Solar-type and low mass stars can be highly active producing flares with energies exceeding erg. Using K2 and TESS data we find no correlation between the number of flares and the rotation phase which is surprising. Our solar flare model can be used to aid our understanding of the origin of flares in other stars. By scaling up our solar model to replicate observed stellar flare energies, we investigate the conditions needed for such high energy flares.

scholarly journals Sigma-1 Receptor Promotes Mitochondrial Bioenergetics by Orchestrating ER Ca2+ Leak during Early ER Stress

Metabolites ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 422
Author(s):  
Zhanat Koshenov ◽  
Furkan E. Oflaz ◽  
Martin Hirtl ◽  
Johannes Pilic ◽  
Olaf A. Bachkoenig ◽  
...  
Keyword(s):  
Er Stress ◽  
Energy Demand ◽  
Molecular Mechanisms ◽  
High Energy ◽  
Human Neuroblastoma Cell ◽  
Mitochondrial Bioenergetics ◽  
Dependent Manner ◽  
Human Neuroblastoma ◽  
Sigma 1 Receptor ◽  
Sigma 1

The endoplasmic reticulum (ER) is a complex, multifunctional organelle of eukaryotic cells and responsible for the trafficking and processing of nearly 30% of all human proteins. Any disturbance to these processes can cause ER stress, which initiates an adaptive mechanism called unfolded protein response (UPR) to restore ER functions and homeostasis. Mitochondrial ATP production is necessary to meet the high energy demand of the UPR, while the molecular mechanisms of ER to mitochondria crosstalk under such stress conditions remain mainly enigmatic. Thus, better understanding the regulation of mitochondrial bioenergetics during ER stress is essential to combat many pathologies involving ER stress, the UPR, and mitochondria. This article investigates the role of Sigma-1 Receptor (S1R), an ER chaperone, has in enhancing mitochondrial bioenergetics during early ER stress using human neuroblastoma cell lines. Our results show that inducing ER stress with tunicamycin, a known ER stressor, greatly enhances mitochondrial bioenergetics in a time- and S1R-dependent manner. This is achieved by enhanced ER Ca2+ leak directed towards mitochondria by S1R during the early phase of ER stress. Our data point to the importance of S1R in promoting mitochondrial bioenergetics and maintaining balanced H2O2 metabolism during early ER stress.

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