SUMO under stress

2008 ◽  
Vol 36 (5) ◽  
pp. 874-878 ◽  
Author(s):  
Denis Tempé ◽  
Marc Piechaczyk ◽  
Guillaume Bossis
Keyword(s):  
Molecular Mechanisms ◽  
Environmental Stresses ◽  
Present Review ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
And Function

During the last decade, SUMOylation has emerged as a central regulatory post-translational modification in the control of the fate and function of proteins. However, how SUMOylation is regulated itself has just started to be delineated. It appears now that SUMO (small ubiquitin-related modifier) conjugation/deconjugation equilibrium is affected by various environmental stresses, including osmotic, hypoxic, heat, oxidative and genotoxic stresses. This regulation occurs either at the level of individual targets, through an interplay between stress-induced phosphorylation and SUMOylation, or via modulation of the conjugation/deconjugation machinery abundance or activity. The present review gives an overview of the connections between stress and SUMOylation, the underlying molecular mechanisms and their effects on cellular functions.

scholarly journals C-terminal tail polyglycylation and polyglutamylation alter microtubule mechanical properties

2019 ◽  
Author(s):  
Kathryn P. Wall ◽  
Harold Hart ◽  
Thomas Lee ◽  
Cynthia Page ◽  
Taviare L. Hawkins ◽  
...  
Keyword(s):  
Mechanical Properties ◽  
Molecular Mechanisms ◽  
High Stress ◽  
Resonance Spectroscopy ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Peptide Backbone ◽  
Post Translational Modifications ◽  
Intrinsic Stiffness ◽  
Insight Into

ABSTRACTMicrotubules are biopolymers that perform diverse cellular functions. The regulation of microtubule behavior occurs in part through post-translational modification of both the α- and β- subunits of tubulin. One class of modifications is the heterogeneous addition of glycine and glutamate residues to the disordered C-terminal tails of tubulin. Due to their prevalence in stable, high stress cellular structures such as cilia, we sought to determine if these modifications alter the intrinsic stiffness of microtubules. Here we describe the purification and characterization of differentially-modified pools of tubulin from Tetrahymena thermophila. We found that glycylation on the α-C-terminal tail is a key determinant of microtubule stiffness, but does not affect the number of protofilaments incorporated into microtubules. We measured the dynamics of the tail peptide backbone using nuclear magnetic resonance spectroscopy. We found that the spin-spin relaxation rate (R2) showed a pronounced decreased as a function of distance from the tubulin surface for the α-tubulin tail, indicating that the α-tubulin tail interacts with the dimer surface. This suggests that the interactions of the α-C-terminal tail with the tubulin body contributes to the stiffness of the assembled microtubule, providing insight into the mechanism by which glycylation and glutamylation can alter microtubule mechanical properties.SIGNIFICANCEMicrotubules are regulated in part by post-translational modifications including the heterogeneous addition of glycine and glutamate residues to the C-terminal tails. By producing and characterizing differentially-modified tubulin, this work provides insight into the molecular mechanisms of how these modifications alter intrinsic microtubule properties such as flexibility. These results have broader implications for mechanisms of how ciliary structures are able to function under high stress.

scholarly journals Recent progress in research on molecular mechanisms of autophagy in the heart

2015 ◽  
Vol 308 (4) ◽  
pp. H259-H268 ◽  
Author(s):  
Yasuhiro Maejima ◽  
Yun Chen ◽  
Mitsuaki Isobe ◽  
Åsa B. Gustafsson ◽  
Richard N. Kitsis ◽  
...  
Keyword(s):  
Heart Disease ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Degradation Process ◽  
Structure And Function ◽  
Cellular Functions ◽  
Evolutionarily Conserved ◽  
And Function ◽  
Cellular Dysfunction

Dysregulation of autophagy, an evolutionarily conserved process for degradation of long-lived proteins and organelles, has been implicated in the pathogenesis of human disease. Recent research has uncovered pathways that control autophagy in the heart and molecular mechanisms by which alterations in this process affect cardiac structure and function. Although initially thought to be a nonselective degradation process, autophagy, as it has become increasingly clear, can exhibit specificity in the degradation of molecules and organelles, such as mitochondria. Furthermore, it has been shown that autophagy is involved in a wide variety of previously unrecognized cellular functions, such as cell death and metabolism. A growing body of evidence suggests that deviation from appropriate levels of autophagy causes cellular dysfunction and death, which in turn leads to heart disease. Here, we review recent advances in understanding the role of autophagy in heart disease, highlight unsolved issues, and discuss the therapeutic potential of modulating autophagy in heart disease.

scholarly journals SIRT2 deacetylase regulates the activity of GSK3 isoforms independent of inhibitory phosphorylation

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Mohsen Sarikhani ◽  
Sneha Mishra ◽  
Sangeeta Maity ◽  
Chaithanya Kotyada ◽  
Donald Wolfgeher ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Serine Phosphorylation ◽  
Glycogen Synthase Kinase 3 ◽  
Lysine Acetylation ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Dynamics Simulations ◽  
And Function ◽  
Reduced Activity ◽  
Deficient Mice

Glycogen synthase kinase 3 (GSK3) is a critical regulator of diverse cellular functions involved in the maintenance of structure and function. Enzymatic activity of GSK3 is inhibited by N-terminal serine phosphorylation. However, alternate post-translational mechanism(s) responsible for GSK3 inactivation are not characterized. Here, we report that GSK3α and GSK3β are acetylated at Lys246 and Lys183, respectively. Molecular modeling and/or molecular dynamics simulations indicate that acetylation of GSK3 isoforms would hinder both the adenosine binding and prevent stable interactions of the negatively charged phosphates. We found that SIRT2 deacetylates GSK3β, and thus enhances its binding to ATP. Interestingly, the reduced activity of GSK3β is associated with lysine acetylation, but not with phosphorylation at Ser9 in hearts of SIRT2-deficient mice. Moreover, GSK3 is required for the anti-hypertrophic function of SIRT2 in cardiomyocytes. Overall, our study identified lysine acetylation as a novel post-translational modification regulating GSK3 activity.

scholarly journals An atlas of Arabidopsis protein S-Acylation reveals its widespread role in plant cell organisation of and function

2020 ◽  
Author(s):  
Manoj Kumar ◽  
Paul Carr ◽  
Simon Turner
Keyword(s):  
Sequence Similarity ◽  
Protein S ◽  
Cysteine Residue ◽  
Cellulose Synthesis ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Ring Type ◽  
Arabidopsis Proteome ◽  
Arabidopsis Protein ◽  
And Function

AbstractS-acylation is the addition of a fatty acid to a cysteine residue of a protein. While this modification may profoundly alter protein behaviour, its effects on the function of plant proteins remains poorly characterised, largely as a result to the lack of basic information regarding which proteins are S-acylated and where in the proteins the modification occurs. In order to address this gap in our knowledge, we have performed a comprehensive analysis of plant protein S-acylation from 6 separate tissues. In our highest confidence group, we identified 5185 cysteines modified by S-acylation, which were located in 4891 unique peptides from 2643 different proteins. This represents around 9% of the entire Arabidopsis proteome and suggests an important role for S-acylation in many essential cellular functions including trafficking, signalling and metabolism. To illustrate the potential of this dataset, we focus on cellulose synthesis and confirm for the first time the S-acylation of all proteins known to be involved in cellulose synthesis and trafficking of the cellulose synthase complex. In the secondary cell walls, cellulose synthesis requires three different catalytic subunits (CESA4, CESA7 and CESA8) that all exhibit striking sequence similarity. While all three proteins have been widely predicted to possess a RING-type zinc finger at their N-terminus, for CESA4 and CESA8, we find evidence for S-acylation of cysteines in this region that is incompatible with any role in coordinating metal ions. We show that while CESA7 may possess a RING type domain, the same region of CESA4 and CESA8 appear to have evolved a very different structure. Together, the data suggests this study represents an atlas of S-acylation in Arabidopsis that will facilitate the broader study of this elusive post-translational modification in plants as well as demonstrates the importance of undertaking further work in this area.

scholarly journals On the Wrong Track: Alterations of Ciliary Transport in Inherited Retinal Dystrophies

2021 ◽  
Vol 9 ◽  
Author(s):  
Laura Sánchez-Bellver ◽  
Vasileios Toulis ◽  
Gemma Marfany
Keyword(s):  
Retinal Degeneration ◽  
Outer Segment ◽  
Molecular Mechanisms ◽  
Photoreceptor Cells ◽  
Cellular Functions ◽  
Inherited Disorders ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Elevated Protein ◽  
And Function

Ciliopathies are a group of heterogeneous inherited disorders associated with dysfunction of the cilium, a ubiquitous microtubule-based organelle involved in a broad range of cellular functions. Most ciliopathies are syndromic, since several organs whose cells produce a cilium, such as the retina, cochlea or kidney, are affected by mutations in ciliary-related genes. In the retina, photoreceptor cells present a highly specialized neurosensory cilium, the outer segment, stacked with membranous disks where photoreception and phototransduction occurs. The daily renewal of the more distal disks is a unique characteristic of photoreceptor outer segments, resulting in an elevated protein demand. All components necessary for outer segment formation, maintenance and function have to be transported from the photoreceptor inner segment, where synthesis occurs, to the cilium. Therefore, efficient transport of selected proteins is critical for photoreceptor ciliogenesis and function, and any alteration in either cargo delivery to the cilium or intraciliary trafficking compromises photoreceptor survival and leads to retinal degeneration. To date, mutations in more than 100 ciliary genes have been associated with retinal dystrophies, accounting for almost 25% of these inherited rare diseases. Interestingly, not all mutations in ciliary genes that cause retinal degeneration are also involved in pleiotropic pathologies in other ciliated organs. Depending on the mutation, the same gene can cause syndromic or non-syndromic retinopathies, thus emphasizing the highly refined specialization of the photoreceptor neurosensory cilia, and raising the possibility of photoreceptor-specific molecular mechanisms underlying common ciliary functions such as ciliary transport. In this review, we will focus on ciliary transport in photoreceptor cells and discuss the molecular complexity underpinning retinal ciliopathies, with a special emphasis on ciliary genes that, when mutated, cause either syndromic or non-syndromic retinal ciliopathies.

scholarly journals Pathophysiological Role of K2P Channels in Human Diseases

2021 ◽  
Vol 55 (S3) ◽  
pp. 65-86
Keyword(s):  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Expression Patterns ◽  
Ion Homeostasis ◽  
Human Diseases ◽  
Cellular Functions ◽  
Aberrant Expression ◽  
K2p Channels ◽  
And Function

The family of two-pore domain potassium (K2P) channels is critically involved in central cellular functions such as ion homeostasis, cell development, and excitability. K2P channels are widely expressed in different human cell types and organs. It is therefore not surprising that aberrant expression and function of K2P channels are related to a spectrum of human diseases, including cancer, autoimmune, CNS, cardiovascular, and urinary tract disorders. Despite homologies in structure, expression, and stimulus, the functional diversity of K2P channels leads to heterogeneous influences on human diseases. The role of individual K2P channels in different disorders depends on expression patterns and modulation in cellular functions. However, an imbalance of potassium homeostasis and action potentials contributes to most disease pathologies. In this review, we provide an overview of current knowledge on the role of K2P channels in human diseases. We look at altered channel expression and function, the potential underlying molecular mechanisms, and prospective research directions in the field of K2P channels.

H2S signaling in redox regulation of cellular functions

2013 ◽  
Vol 91 (1) ◽  
pp. 8-14 ◽  
Author(s):  
Youngjun Ju ◽  
Weihua Zhang ◽  
Yanxi Pei ◽  
Guangdong Yang
Keyword(s):  
Mammalian Cells ◽  
Redox Regulation ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Redox Homeostasis ◽  
Therapeutic Interventions ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Future Design ◽  
Cellular Effects

Hydrogen sulfide (H2S) is traditionally recognized as a toxic gas with a rotten-egg smell. In just the last few decades, H2S has been found to be one of a family of gasotransmitters, together with nitric oxide and carbon monoxide, and various physiologic effects of H2S have been reported. Among the most acknowledged molecular mechanisms for the cellular effects of H2S is the regulation of intracellular redox homeostasis and post-translational modification of proteins through S-sulfhydration. On the one side, H2S can promote an antioxidant effect and is cytoprotective; on the other side, H2S stimulates oxidative stress and is cytotoxic. This review summarizes our current knowledge of the antioxidant versus pro-oxidant effects of H2S in mammalian cells and describes the Janus-faced properties of this novel gasotransmitter. The redox regulation for the cellular effects of H2S through S-sulfhydration and the role of H2S in glutathione generation is also recapitulated. A better understanding of H2S-regualted redox homeostasis will pave the way for future design of novel pharmacological and therapeutic interventions for various diseases.

scholarly journals Munc13-4 interacts with syntaxin 7 and regulates late endosomal maturation, endosomal signaling, and TLR9-initiated cellular responses

2016 ◽  
Vol 27 (3) ◽  
pp. 572-587 ◽  
Author(s):  
Jing He ◽  
Jennifer L. Johnson ◽  
Jlenia Monfregola ◽  
Mahalakshmi Ramadass ◽  
Kersi Pestonjamasp ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Direct Evidence ◽  
Innate Immune ◽  
Cellular Functions ◽  
Late Endosomes ◽  
Endosomal Signaling ◽  
Endocytic Machinery ◽  
Live Cell Microscopy ◽  
And Function ◽  
Cell Microscopy

The molecular mechanisms that regulate late endosomal maturation and function are not completely elucidated, and direct evidence of a calcium sensor is lacking. Here we identify a novel mechanism of late endosomal maturation that involves a new molecular interaction between the tethering factor Munc13-4, syntaxin 7, and VAMP8. Munc13-4 binding to syntaxin 7 was significantly increased by calcium. Colocalization of Munc13-4 and syntaxin 7 at late endosomes was demonstrated by high-resolution and live-cell microscopy. Munc13-4–deficient cells show increased numbers of significantly enlarged late endosomes, a phenotype that was mimicked by the fusion inhibitor chloroquine in wild-type cells and rescued by expression of Munc13-4 but not by a syntaxin 7–binding–deficient mutant. Late endosomes from Munc13-4-KO neutrophils show decreased degradative capacity. Munc13-4–knockout neutrophils show impaired endosomal-initiated, TLR9-dependent signaling and deficient TLR9-specific CD11b up-regulation. Thus we present a novel mechanism of late endosomal maturation and propose that Munc13-4 regulates the late endocytic machinery and late endosomal–associated innate immune cellular functions.

Protein kinase Cδ and apoptosis

2007 ◽  
Vol 35 (5) ◽  
pp. 1001-1004 ◽  
Author(s):  
M.E. Reyland
Keyword(s):  
Protein Kinase ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Nuclear Accumulation ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Caspase Cleavage ◽  
Kinase C ◽  
Pkc Protein Kinase C ◽  
Apoptotic Activity

The PKC (protein kinase C) family regulates diverse cellular functions and specific isoforms have been shown to be critical regulators of cell proliferation and survival. In particular, PKCδ is known to be a critical pro-apoptotic signal in many cell types. Work in our laboratory has focused on understanding the molecular mechanisms through which PKCδ regulates apoptosis and on how the pro-apoptotic activity of this ubiquitous kinase is regulated such that cells only activate the apoptotic cascade when appropriate. We have identified multiple regulatory steps that activate the pro-apoptotic function of PKCδ in response to genotoxins. Our studies show that apoptotic signals induce rapid post-translational modification of PKCδ in the regulatory domain, which facilitates translocation of the kinase from the cytoplasm to the nucleus. Active caspase 3 also accumulates in the nucleus under these conditions, resulting in caspase cleavage of PKCδ and generation of a constitutively activated form of PKCδ [δCF (PKCδ catalytic fragment)]. In contrast with PKCδ, δCF is constitutively present in the nucleus, and this nuclear accumulation of PKCδ is essential for apoptosis. Thus our studies suggest that tight regulation of nuclear import and of PKCδ is critical for cell survival and that caspase cleavage of PKCδ in the nucleus signals an irreversible commitment to apoptosis.

DUBs, the regulation of cell identity and disease

2014 ◽  
Vol 465 (1) ◽  
pp. 1-26 ◽  
Author(s):  
Johanna Heideker ◽  
Ingrid E. Wertz
Keyword(s):  
Drug Targets ◽  
Molecular Mechanisms ◽  
Cell Communication ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Cell Identity ◽  
Receptor Signalling ◽  
Future Success ◽  
Potential Drug Targets

The post-translational modification of proteins with ubiquitin represents a complex signalling system that co-ordinates essential cellular functions, including proteolysis, DNA repair, receptor signalling and cell communication. DUBs (deubiquitinases), the enzymes that disassemble ubiquitin chains and remove ubiquitin from proteins, are central to this system. Reflecting the complexity and versatility of ubiquitin signalling, DUB activity is controlled in multiple ways. Although several lines of evidence indicate that aberrant DUB function may promote human disease, the underlying molecular mechanisms are often unclear. Notwithstanding, considerable interest in DUBs as potential drug targets has emerged over the past years. The future success of DUB-based therapy development will require connecting the basic science of DUB function and enzymology with drug discovery. In the present review, we discuss new insights into DUB activity regulation and their links to disease, focusing on the role of DUBs as regulators of cell identity and differentiation, and discuss their potential as emerging drug targets.

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