scholarly journals Sumoylation of the budding yeast kinetochore protein Ndc10 is required for Ndc10 spindle localization and regulation of anaphase spindle elongation

2006 ◽  
Vol 174 (5) ◽  
pp. 653-663 ◽  
Author(s):  
Ben Montpetit ◽  
Tony R. Hazbun ◽  
Stanley Fields ◽  
Philip Hieter
Keyword(s):  
Protein Function ◽  
Budding Yeast ◽  
Chromosome Instability ◽  
Critical Role ◽  
Mitotic Checkpoint ◽  
Kinetochore Protein ◽  
Cellular Processes ◽  
Potential Link ◽  
Important Regulator ◽  
Spindle Elongation

Posttranslational modification by the ubiquitin-like protein SUMO (small ubiquitin-like modifier) is emerging as an important regulator in many cellular processes, including genome integrity. In this study, we show that the kinetochore proteins Ndc10, Bir1, Ndc80, and Cep3, which mediate the attachment of chromosomes to spindle microtubules, are sumoylated substrates in budding yeast. Furthermore, we show that Ndc10, Bir1, and Cep3 but not Ndc80 are desumoylated upon exposure to nocodazole, highlighting the possibility of distinct roles for sumoylation in modulating kinetochore protein function and of a potential link between the sumoylation of kinetochore proteins and mitotic checkpoint function. We find that lysine to arginine mutations that eliminate the sumoylation of Ndc10 cause chromosome instability, mislocalization of Ndc10 from the mitotic spindle, abnormal anaphase spindles, and a loss of Bir1 sumoylation. These data suggest that sumoylation of Ndc10 and other kinetochore proteins play a critical role during the mitotic process.

scholarly journals The Canonical Wnt Pathway as a Key Regulator in Liver Development, Differentiation and Homeostatic Renewal

Genes ◽  
2020 ◽  
Vol 11 (10) ◽  
pp. 1163
Author(s):  
Sebastian L. Wild ◽  
Aya Elghajiji ◽  
Carmen Grimaldos Rodriguez ◽  
Stephen D. Weston ◽  
Zoë D. Burke ◽  
...  
Keyword(s):  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Signalling Pathway ◽  
Fate Specification ◽  
Cellular Processes ◽  
Recent Developments ◽  
Body Patterning ◽  
Important Regulator ◽  
Canonical Wnt

The canonical Wnt (Wnt/β-catenin) signalling pathway is highly conserved and plays a critical role in regulating cellular processes both during development and in adult tissue homeostasis. The Wnt/β-catenin signalling pathway is vital for correct body patterning and is involved in fate specification of the gut tube, the primitive precursor of liver. In adults, the Wnt/β-catenin pathway is increasingly recognised as an important regulator of metabolic zonation, homeostatic renewal and regeneration in response to injury throughout the liver. Herein, we review recent developments relating to the key role of the pathway in the patterning and fate specification of the liver, in the directed differentiation of pluripotent stem cells into hepatocytes and in governing proliferation and zonation in the adult liver. We pay particular attention to recent contributions to the controversy surrounding homeostatic renewal and proliferation in response to injury. Furthermore, we discuss how crosstalk between the Wnt/β-catenin and Hedgehog (Hh) and hypoxia inducible factor (HIF) pathways works to maintain liver homeostasis. Advancing our understanding of this pathway will benefit our ability to model disease, screen drugs and generate tissue and organ replacements for regenerative medicine.

scholarly journals Glutamate 73 Promotes Anti-arrhythmic Effects of Voltage-Dependent Anion Channel Through Regulation of Mitochondrial Ca2+ Uptake

2021 ◽  
Vol 12 ◽  
Author(s):  
Hirohito Shimizu ◽  
Simon Huber ◽  
Adam D. Langenbacher ◽  
Lauren Crisman ◽  
Jie Huang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Critical Role ◽  
Anion Channel ◽  
Outer Mitochondrial Membrane ◽  
Voltage Dependent Anion Channel ◽  
Rescue Effect ◽  
Cellular Processes ◽  
Voltage Dependent ◽  
Important Regulator ◽  
Cellular Ca

Mitochondria critically regulate a range of cellular processes including bioenergetics, cellular metabolism, apoptosis, and cellular Ca2+ signaling. The voltage-dependent anion channel (VDAC) functions as a passageway for the exchange of ions, including Ca2+, across the outer mitochondrial membrane. In cardiomyocytes, genetic or pharmacological activation of isoform 2 of VDAC (VDAC2) effectively potentiates mitochondrial Ca2+ uptake and suppresses Ca2+ overload-induced arrhythmogenic events. However, molecular mechanisms by which VDAC2 controls mitochondrial Ca2+ transport and thereby influences cardiac rhythmicity remain elusive. Vertebrates express three highly homologous VDAC isoforms. Here, we used the zebrafish tremblor/ncx1h mutant to dissect the isoform-specific roles of VDAC proteins in Ca2+ handling. We found that overexpression of VDAC1 or VDAC2, but not VDAC3, suppresses the fibrillation-like phenotype in zebrafish tremblor/ncx1h mutants. A chimeric approach showed that moieties in the N-terminal half of VDAC are responsible for their divergent functions in cardiac biology. Phylogenetic analysis further revealed that a glutamate at position 73, which was previously described to be an important regulator of VDAC function, is sevolutionarily conserved in VDAC1 and VDAC2, whereas a glutamine occupies position 73 (Q73) of VDAC3. To investigate whether E73/Q73 determines VDAC isoform-specific anti-arrhythmic effect, we mutated E73 to Q in VDAC2 (VDAC2E73Q) and Q73 to E in VDAC3 (VDAC3Q73E). Interestingly, VDAC2E73Q failed to restore rhythmic cardiac contractions in ncx1 deficient hearts, while the Q73E conversion induced a gain of function in VDAC3. In HL-1 cardiomyocytes, VDAC2 knockdown diminished the transfer of Ca2+ from the SR into mitochondria and overexpression of VDAC2 or VDAC3Q73E restored SR-mitochondrial Ca2+ transfer in VDAC2 deficient HL-1 cells, whereas this rescue effect was absent for VDAC3 and drastically compromised for VDAC2E73Q. Collectively, our findings demonstrate a critical role for the evolutionary conserved E73 in determining the anti-arrhythmic effect of VDAC isoforms through modulating Ca2+ cross-talk between the SR and mitochondria in cardiomyocytes.

scholarly journals Arginine Decarboxylase Is Essential for Pneumococcal Stress Responses

Pathogens ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 286
Author(s):  
Mary Frances Nakamya ◽  
Moses B. Ayoola ◽  
Leslie A. Shack ◽  
Mirghani Mohamed ◽  
Edwin Swiatlo ◽  
...  
Keyword(s):  
Stress Responses ◽  
Critical Role ◽  
Acid Stress ◽  
Arginine Decarboxylase ◽  
Arginine Deiminase ◽  
Dependent Manner ◽  
Cellular Processes ◽  
Opportunistic Human Pathogen ◽  
Thiol Peroxidase ◽  
The Impact

Polyamines such as putrescine, cadaverine, and spermidine are small cationic molecules that play significant roles in cellular processes, including bacterial stress responses and host–pathogen interactions. Streptococcus pneumoniae is an opportunistic human pathogen, which causes several diseases that account for significant morbidity and mortality worldwide. As it transits through different host niches, S. pneumoniae is exposed to and must adapt to different types of stress in the host microenvironment. We earlier reported that S. pneumoniae TIGR4, which harbors an isogenic deletion of an arginine decarboxylase (ΔspeA), an enzyme that catalyzes the synthesis of agmatine in the polyamine synthesis pathway, has a reduced capsule. Here, we report the impact of arginine decarboxylase deletion on pneumococcal stress responses. Our results show that ΔspeA is more susceptible to oxidative, nitrosative, and acid stress compared to the wild-type strain. Gene expression analysis by qRT-PCR indicates that thiol peroxidase, a scavenger of reactive oxygen species and aguA from the arginine deiminase system, could be important for peroxide stress responses in a polyamine-dependent manner. Our results also show that speA is essential for endogenous hydrogen peroxide and glutathione production in S. pneumoniae. Taken together, our findings demonstrate the critical role of arginine decarboxylase in pneumococcal stress responses that could impact adaptation and survival in the host.

scholarly journals TFEB Signalling-Related MicroRNAs and Autophagy

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 985
Author(s):  
Davide Corà ◽  
Federico Bussolino ◽  
Gabriella Doronzo
Keyword(s):  
Transcriptional Regulation ◽  
Stress Factors ◽  
Cellular Functions ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Factor Deficiency ◽  
Transcription Factor Eb ◽  
Important Regulator ◽  
Response To Stress ◽  
Post Transcriptional Regulation

The oncogenic Transcription Factor EB (TFEB), a member of MITF-TFE family, is known to be the most important regulator of the transcription of genes responsible for the control of lysosomal biogenesis and functions, autophagy, and vesicles flux. TFEB activation occurs in response to stress factors such as nutrient and growth factor deficiency, hypoxia, lysosomal stress, and mitochondrial damage. To reach the final functional status, TFEB is regulated in multimodal ways, including transcriptional rate, post-transcriptional regulation, and post-translational modifications. Post-transcriptional regulation is in part mediated by miRNAs. miRNAs have been linked to many cellular processes involved both in physiology and pathology, such as cell migration, proliferation, differentiation, and apoptosis. miRNAs also play a significant role in autophagy, which exerts a crucial role in cell behaviour during stress or survival responses. In particular, several miRNAs directly recognise TFEB transcript or indirectly regulate its function by targeting accessory molecules or enzymes involved in its post-translational modifications. Moreover, the transcriptional programs triggered by TFEB may be influenced by the miRNA-mediated regulation of TFEB targets. Finally, recent important studies indicate that the transcription of many miRNAs is regulated by TFEB itself. In this review, we describe the interplay between miRNAs with TFEB and focus on how these types of crosstalk affect TFEB activation and cellular functions.

scholarly journals Key phosphorylation events in Spc29 and Spc42 guide multiple steps of yeast centrosome duplication

2018 ◽  
Vol 29 (19) ◽  
pp. 2280-2291 ◽  
Author(s):  
Michele Haltiner Jones ◽  
Eileen T. O’Toole ◽  
Amy S. Fabritius ◽  
Eric G. Muller ◽  
Janet B. Meehl ◽  
...  
Keyword(s):  
Cell Cycle Progression ◽  
Spindle Pole Body ◽  
Spindle Pole ◽  
Centrosome Duplication ◽  
Phosphorylation Sites ◽  
Cycle Progression ◽  
Cellular Processes ◽  
Pole Body ◽  
Core Components ◽  
Spindle Elongation

Phosphorylation modulates many cellular processes during cell cycle progression. The yeast centrosome (called the spindle pole body, SPB) is regulated by the protein kinases Mps1 and Cdc28/Cdk1 as it nucleates microtubules to separate chromosomes during mitosis. Previously we completed an SPB phosphoproteome, identifying 297 sites on 17 of the 18 SPB components. Here we describe mutagenic analysis of phosphorylation events on Spc29 and Spc42, two SPB core components that were shown in the phosphoproteome to be heavily phosphorylated. Mutagenesis at multiple sites in Spc29 and Spc42 suggests that much of the phosphorylation on these two proteins is not essential but enhances several steps of mitosis. Of the 65 sites examined on both proteins, phosphorylation of the Mps1 sites Spc29-T18 and Spc29-T240 was shown to be critical for function. Interestingly, these two sites primarily influence distinct successive steps; Spc29-T240 is important for the interaction of Spc29 with Spc42, likely during satellite formation, and Spc29-T18 facilitates insertion of the new SPB into the nuclear envelope and promotes anaphase spindle elongation. Phosphorylation sites within Cdk1 motifs affect function to varying degrees, but mutations only have significant effects in the presence of an MPS1 mutation, supporting a theme of coregulation by these two kinases.

Cdc28-Clb mitotic kinase negatively regulates bud site assembly in the budding yeast

2001 ◽  
Vol 114 (1) ◽  
pp. 207-218 ◽  
Author(s):  
C.G. Padmashree ◽  
U. Surana
Keyword(s):  
Kinase Activity ◽  
Budding Yeast ◽  
Critical Role ◽  
The Other ◽  
Yeast Saccharomyces Cerevisiae ◽  
Bud Formation ◽  
Temporal Regulation ◽  
Mitotic Kinase ◽  
Cortical Localization ◽  
Bud Site

In the budding yeast Saccharomyces cerevisiae, a prospective mother normally commences the formation of a daughter (the bud) only in the G(1) phase of the cell division cycle. This suggests a strict temporal regulation of the processes that initiate the formation of a new bud. Using cortical localization of bud site components Spa2 and Bni1 as an indicator of bud site assembly, we show that cells assemble a bud site following inactivation of the Cdc28-Clb mitotic kinase but prior to START. Interestingly, an untimely inactivation of the mitotic kinase is sufficient to drive cells to assemble a new bud site inappropriately in G(2) or M phases. The induction of Cdc28/Clb kinase activity in G(1), on the other hand, dramatically reduces a cell's ability to construct an incipient bud site. Our findings strongly suggest that the Cdc28-Clb kinase plays a critical role in the mechanism that restricts the timing of bud formation to the G(1) phase of the cell cycle.

scholarly journals Effects of Chemical Mixtures on the Ovary

Reproduction ◽  
2021 ◽  
Author(s):  
Vasiliki E. Mourikes ◽  
Jodi A Flaws
Keyword(s):  
Ovarian Development ◽  
Steroid Hormone ◽  
Critical Role ◽  
Corpora Lutea ◽  
Chemical Mixtures ◽  
Hormone Production ◽  
Sex Steroid Hormone ◽  
Cellular Processes ◽  
Female Reproductive Health

The ovaries play a critical role in female reproductive health because they are the site of oocyte maturation and sex steroid hormone production. The unique cellular processes that take place within the ovary make it a susceptible target for chemical mixtures. Herein, we review the available data regarding the effects of chemical mixtures on the ovary, focusing on development, folliculogenesis, and steroidogenesis. The chemical mixtures discussed include those to which women are exposed to environmentally, occupationally, and medically. Following a brief introduction to chemical mixture components, we describe the effects of chemical mixtures on ovarian development, folliculogenesis, and steroidogenesis. Further, we discuss the effects of chemical mixtures on corpora lutea and transgenerational outcomes. Identifying the effects of chemical mixtures on the ovaries is paramount to preventing and treating mixture-inducing toxicity of the ovary that has long-term consequences such as infertility and ovarian disease.

scholarly journals Arabidopsis ALIX is required for the endosomal localization of the deubiquitinating enzyme AMSH3

2015 ◽  
Vol 112 (40) ◽  
pp. E5543-E5551 ◽  
Author(s):  
Kamila Kalinowska ◽  
Marie-Kristin Nagel ◽  
Kaija Goodman ◽  
Laura Cuyas ◽  
Franziska Anzenberger ◽  
...  
Keyword(s):  
Cellular Level ◽  
Deubiquitinating Enzymes ◽  
Interacting Protein ◽  
Endosomal Sorting ◽  
Cellular Processes ◽  
Late Endosomes ◽  
Knockout Mutants ◽  
Important Regulator

Ubiquitination is a signal for various cellular processes, including for endocytic degradation of plasma membrane cargos. Ubiquitinating as well as deubiquitinating enzymes (DUBs) can regulate these processes by modifying the ubiquitination status of target protein. Although accumulating evidence points to the important regulatory role of DUBs, the molecular basis of their regulation is still not well understood. Associated molecule with the SH3 domain of signal transduction adaptor molecule (STAM) (AMSH) is a conserved metalloprotease DUB in eukaryotes. AMSH proteins interact with components of the endosomal sorting complex required for transport (ESCRT) and are implicated in intracellular trafficking. To investigate how the function of AMSH is regulated at the cellular level, we carried out an interaction screen for the Arabidopsis AMSH proteins and identified the Arabidopsis homolog of apoptosis-linked gene-2 interacting protein X (ALIX) as a protein interacting with AMSH3 in vitro and in vivo. Analysis of alix knockout mutants in Arabidopsis showed that ALIX is essential for plant growth and development and that ALIX is important for the biogenesis of the vacuole and multivesicular bodies (MVBs). Cell biological analysis revealed that ALIX and AMSH3 colocalize on late endosomes. Although ALIX did not stimulate AMSH3 activity in vitro, in the absence of ALIX, AMSH3 localization on endosomes was abolished. Taken together, our data indicate that ALIX could function as an important regulator for AMSH3 function at the late endosomes.

The protease MBTPS2 is an important regulator of several cellular processes, especially in health and sickness

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Active Sites ◽  
Peptide Bond ◽  
Cellular Processes ◽  
Disease States ◽  
Tremendous Progress ◽  
Catalytic Sites ◽  
Important Regulator ◽  
Catalytic Active Sites ◽  
Proteolytic Action ◽  
Health And Sickness

Since the identification of MBTPS2 in 1997, tremendous progress has been made in determining the protease's functions. The protease has developed from an element of the SREBP cleavage machinery to an important regulator of several cellular processes, especially in health and sickness. With this newfound information from biochemical and structural biology, S2P's proteolytic action through peptide bond hydrolysis can occur in the membrane, providing a conceptual framework for appreciating S2P's roles in other aspects, and showing that many other substrates rely on S2P for their survival. In addition, we discovered the identity of both of S2P's catalytic active sites, an essential finding as the activity of the proteolysis as well as the pathogenesis of MBTPS2-caused illnesses seems to be connected to the molecular and biochemical features of the catalytic sites. Additionally, MBTPS2 causes different diseases, possibly illustrating the pleiotropic nature of the protein. Also, while the ailments reported thus far are all due to mutations that cause MBTPS2 to lose function, other variants that cause MBTPS2 to be hyperactive have not been examined. Nevertheless, recognizing the related sickness pathomechanism is a challenge. Pursuing these challenging technical areas would most definitely enhance our understanding of MBTPS2 in disease states. MBTPS2 appears to be nearing the solution to many of the remaining fundamental questions surrounding the mechanism of its action, as well as being a therapeutic target for new therapies.

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