Lysine modifications and autophagy

2012 ◽  
Vol 52 ◽  
pp. 65-77 ◽  
Author(s):  
Kristi L. Norris ◽  
Tso-Pang Yao
Keyword(s):  
Cellular Stress ◽  
Nutrient Deprivation ◽  
Substrate Selectivity ◽  
Catabolic Pathway ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Lysine Residues ◽  
Clinical Potential ◽  
Insight Into

Nutrient deprivation or cellular stress leads to the activation of a catabolic pathway that is conserved across species, known as autophagy. This process is considered to be adaptive and plays an important role in a number of cellular processes, including metabolism, immunity and development. Autophagy has also been linked to diseases, such as cancer and neurodegeneration, highlighting the importance of a better insight into its regulation. In the present chapter, we discuss how PTMs (post-translational modifications) of lysine residues by acetylation and ubiquitination alter the function of key proteins involved in the activation, maturation and substrate selectivity of autophagy. We also discuss the clinical potential of targeting these modifications to modulate autophagic activities.

scholarly journals Omic-Sig: Utilizing Omics Data to Explore and Visualize Kinase-Substrate Interactions

2019 ◽  
Author(s):  
T. Mamie Lih ◽  
David J. Clark ◽  
Hui Zhang
Keyword(s):  
Protein Phosphorylation ◽  
Software Tool ◽  
Omics Data ◽  
Additional Insight ◽  
Post Translational Modifications ◽  
Kinase Substrate ◽  
Cellular Processes ◽  
Visualization Software ◽  
And Control ◽  
Insight Into

AbstractProtein phosphorylation is one of the most prevalent post-translational modifications, resulting from the activity of protein kinases phosphorylating specific substrates. Multiple cellular processes are regulated via protein phosphorylation, with aberrant signaling driven by dysregulation of phosphorylation events and associating with disease progression (e.g., cancer). Mass spectrometry-based phosphoprotomics approaches can be leveraged for studying alterations of kinase-substrate activity in clinical cohorts. However, the information gained via interrogation of global proteomes and transcriptomes can offer additional insight into the interaction of kinases and their respective substrates. Therefore, we have developed the bioinformatics, data visualization software tool, Omic-Sig, which can stratify prominent phospho-substrates and their associated kinases based on differential abundances between case and control samples (e.g., tumors and their normal adjacent tissues from a cancer cohort) in a multi-omics fashion. Omic-Sig is available at https://github.com/hzhangjhu/Omic-Sig.

scholarly journals SUMOylation Regulates TDP-43 Splicing Activity and Nucleocytoplasmic Distribution

2021 ◽  
Author(s):  
AnnaMaria Maraschi ◽  
Valentina Gumina ◽  
Jessica Dragotto ◽  
Claudia Colombrita ◽  
Miguel Mompeán ◽  
...  
Keyword(s):  
Cellular Localization ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Exon Skipping ◽  
Nucleocytoplasmic Transport ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Lysine Residues ◽  
Regulatory Effects ◽  
Nucleocytoplasmic Distribution

AbstractThe nuclear RNA-binding protein TDP-43 forms abnormal cytoplasmic aggregates in the brains of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients and several molecular mechanisms promoting TDP-43 cytoplasmic mislocalization and aggregation have been proposed, including defects in nucleocytoplasmic transport, stress granules (SG) disassembly and post-translational modifications (PTM). SUMOylation is a PTM which regulates a variety of cellular processes and, similarly to ubiquitination, targets lysine residues. To investigate the possible regulatory effects of SUMOylation on TDP-43 activity and trafficking, we first assessed that TDP-43 is SUMO-conjugated in the nuclear compartment both covalently and non-covalently in the RRM1 domain at the predicted lysine 136 and SUMO-interacting motif (SIM, 106–110 residues), respectively. By using the SUMO-mutant TDP-43 K136R protein, we demonstrated that SUMOylation modifies TDP-43 splicing activity, specifically exon skipping, and influences its sub-cellular localization and recruitment to SG after oxidative stress. When promoting deSUMOylation by SENP1 enzyme over-expression or by treatment with the cell-permeable SENP1 peptide TS-1, the cytoplasmic localization of TDP-43 increased, depending on its SUMOylation. Moreover, deSUMOylation by TS-1 peptide favoured the formation of small cytoplasmic aggregates of the C-terminal TDP-43 fragment p35, still containing the SUMO lysine target 136, but had no effect on the already formed p25 aggregates. Our data suggest that TDP-43 can be post-translationally modified by SUMOylation which may regulate its splicing function and trafficking, indicating a novel and druggable mechanism to explore as its dysregulation may lead to TDP-43 pathological aggregation in ALS and FTD.

scholarly journals SUMOylation Regulates TDP-43 Splicing Activity and Nucleocytoplasmic Distribution

2021 ◽  
Author(s):  
AnnaMaria Maraschi ◽  
Valentina Gumina ◽  
Jessica Dragotto ◽  
Claudia Colombrita ◽  
Miguel Monpeán ◽  
...  
Keyword(s):  
Cellular Localization ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Exon Skipping ◽  
Nucleocytoplasmic Transport ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Lysine Residues ◽  
Regulatory Effects ◽  
Nucleocytoplasmic Distribution

Abstract The nuclear RNA-binding protein TDP-43 forms abnormal cytoplasmic aggregates in the brains of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients and several molecular mechanisms promoting TDP-43 cytoplasmic mislocalization and aggregation have been proposed, including defects in nucleocytoplasmic transport, stress granules (SG) disassembly and post-translational modifications (PTM). SUMOylation is a PTM which regulates a variety of cellular processes and, similarly to ubiquitination, targets lysine residues. To investigate the possible regulatory effects of SUMOylation on TDP-43 activity and trafficking, we first assessed that TDP-43 is SUMO-conjugated in the nuclear compartment both covalently and non-covalently in the RRM1 domain at the predicted lysine 136 and SUMO-interacting motif (SIM, 106–110 residues), respectively. By using the SUMO-mutant TDP-43 K136R protein, we demonstrated that SUMOylation modifies TDP-43 splicing activity, specifically exon skipping, and influences its sub-cellular localization and recruitment to SG after oxidative stress. When promoting deSUMOylation by SENP1 enzyme over-expression or by treatment with the cell-permeable SENP1 peptide TS-1, the cytoplasmic localization of TDP-43 increased, depending on its SUMOylation. Moreover, deSUMOylation by TS-1 peptide favoured the formation of small cytoplasmic aggregates of the C-terminal TDP-43 fragment p35, still containing the SUMO lysine target 136, but had no effect on the already formed p25 aggregates. Our data suggest that TDP-43 can be post-translationally modified by SUMOylation which may regulate its splicing function and trafficking, indicating a novel and druggable mechanism to explore as its dysregulation may lead to TDP-43 pathological aggregation in ALS and FTD.

scholarly journals Identification of Lysine Isobutyrylation as A New Histone Modification Mark

2020 ◽  
Author(s):  
Zhesi Zhu ◽  
Zhen Han ◽  
Levon Halabelian ◽  
Xiangkun Yang ◽  
Jun Ding ◽  
...  
Keyword(s):  
Structural Isomer ◽  
Acid Oxidation ◽  
Rna Seq ◽  
Cellular Processes ◽  
Expression Of Genes ◽  
Eukaryotic Proteins ◽  
Lysine Residues ◽  
Branched Chain ◽  
Insight Into ◽  
Histone Modification Mark

AbstractShort-chain acylation of lysine residues in eukaryotic proteins are recognized as essential posttranslational chemical modifications (PTMs) that regulate cellular processes from transcription, cell cycle, metabolism, to signal transduction. Lysine butyrylation was initially discovered as a normal straight chain butyrylation (Knbu). Here we report its structural isomer, branched chain butyrylation, i.e. lysine isobutyrylation (Kibu), existing as a new PTM on nuclear histones. Uniquely, isobutyryl-CoA is derived from valine catabolism and branched chain fatty acid oxidation which is distinct from the metabolism of n-butyryl-CoA. Several histone acetyltransferases were found to possess lysine isobutyryltransferase activity, especially p300 and HAT1. We resolved the X-ray crystal structures of HAT1 in complex with isobutyryl-CoA that gleaned an atomic level insight into HAT-catalyzed isobutyrylation. RNA-Seq profiling revealed that isobutyrate greatly affected the expression of genes associated with many pivotal biological pathways. Our findings identify Kibu as a novel chemical modification mark in histones and suggest its extensive role in regulating epigenetics and cellular physiology.

scholarly journals Structure, Activity, and Function of the Protein Lysine Methyltransferase G9a

Life ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1082
Author(s):  
Coralie Poulard ◽  
Lara M. Noureddine ◽  
Ludivine Pruvost ◽  
Muriel Le Romancer
Keyword(s):  
Transcriptional Repression ◽  
Cancer Biology ◽  
Structural Features ◽  
Cellular Mechanisms ◽  
Post Translational Modifications ◽  
Structure Activity ◽  
Lysine Residues ◽  
Lysine Methyltransferase ◽  
And Function ◽  
Insight Into

G9a is a lysine methyltransferase catalyzing the majority of histone H3 mono- and dimethylation at Lys-9 (H3K9), responsible for transcriptional repression events in euchromatin. G9a has been shown to methylate various lysine residues of non-histone proteins and acts as a coactivator for several transcription factors. This review will provide an overview of the structural features of G9a and its paralog called G9a-like protein (GLP), explore the biochemical features of G9a, and describe its post-translational modifications and the specific inhibitors available to target its catalytic activity. Aside from its role on histone substrates, the review will highlight some non-histone targets of G9a, in order gain insight into their role in specific cellular mechanisms. Indeed, G9a was largely described to be involved in embryonic development, hypoxia, and DNA repair. Finally, the involvement of G9a in cancer biology will be presented.

scholarly journals Function of Centriolar Satellites and Regulation by Post-Translational Modifications

2021 ◽  
Vol 9 ◽  
Author(s):  
Clotilde C. N. Renaud ◽  
Nicolas Bidère
Keyword(s):  
Primary Cilia ◽  
Cellular Stress ◽  
Complex Nature ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Recent Advances ◽  
Dynamic Structures

Centriolar satellites are small membrane-less granules that gravitate around the centrosome. Recent advances in defining the satellite proteome and interactome have unveiled hundreds of new satellite components thus illustrating the complex nature of these particles. Although initially linked to the homeostasis of centrosome and the formation of primary cilia, these composite and highly dynamic structures appear to participate in additional cellular processes, such as proteostasis, autophagy, and cellular stress. In this review, we first outline the main features and many roles of centriolar satellites. We then discuss how post-translational modifications, such as phosphorylation and ubiquitination, shape their composition and functions. This is of particular interest as interfering with these processes may provide ways to manipulate these structures.

scholarly journals Identification of lysine isobutyrylation as a new histone modification mark

2020 ◽  
Author(s):  
Zhesi Zhu ◽  
Zhen Han ◽  
Levon Halabelian ◽  
Xiangkun Yang ◽  
Jun Ding ◽  
...  
Keyword(s):  
Structural Isomer ◽  
Acid Oxidation ◽  
Rna Seq ◽  
Cellular Processes ◽  
Expression Of Genes ◽  
Eukaryotic Proteins ◽  
Lysine Residues ◽  
Branched Chain ◽  
Insight Into

Abstract Short-chain acylations of lysine residues in eukaryotic proteins are recognized as essential posttranslational chemical modifications (PTMs) that regulate cellular processes from transcription, cell cycle, metabolism, to signal transduction. Lysine butyrylation was initially discovered as a normal straight chain butyrylation (Knbu). Here we report its structural isomer, branched chain butyrylation, i.e. lysine isobutyrylation (Kibu), existing as a new PTM on nuclear histones. Uniquely, isobutyryl-CoA is derived from valine catabolism and branched chain fatty acid oxidation which is distinct from the metabolism of n-butyryl-CoA. Several histone acetyltransferases were found to possess lysine isobutyryltransferase activity in vitro, especially p300 and HAT1. Transfection and western blot experiments showed that p300 regulated histone isobutyrylation levels in the cell. We resolved the X-ray crystal structures of HAT1 in complex with isobutyryl-CoA that gleaned an atomic level insight into HAT-catalyzed isobutyrylation. RNA-Seq profiling revealed that isobutyrate greatly affected the expression of genes associated with many pivotal biological pathways. Together, our findings identify Kibu as a novel chemical modification mark in histones and suggest its extensive role in regulating epigenetics and cellular physiology.

scholarly journals RSK1 SUMOylation is required for KSHV lytic replication

2021 ◽  
Vol 17 (12) ◽  
pp. e1010123
Author(s):  
Zhenshan Liu ◽  
Chengrong Liu ◽  
Xin Wang ◽  
Wenwei Li ◽  
Jingfan Zhou ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Mapk Pathway ◽  
Amino Acid Position ◽  
Lytic Replication ◽  
Wild Type ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Phosphorylation Level ◽  
Lysine Residues ◽  
Substrate Phosphorylation

RSK1, a downstream kinase of the MAPK pathway, has been shown to regulate multiple cellular processes and is essential for lytic replication of a variety of viruses, including Kaposi’s sarcoma-associated herpesvirus (KSHV). Besides phosphorylation, it is not known whether other post-translational modifications play an important role in regulating RSK1 function. We demonstrate that RSK1 undergoes robust SUMOylation during KSHV lytic replication at lysine residues K110, K335, and K421. SUMO modification does not alter RSK1 activation and kinase activity upon KSHV ORF45 co-expression, but affects RSK1 downstream substrate phosphorylation. Compared to wild-type RSK1, the overall phosphorylation level of RxRxxS*/T* motif is significantly declined in RSK1K110/335/421R expressing cells. Specifically, SUMOylation deficient RSK1 cannot efficiently phosphorylate eIF4B. Sequence analysis showed that eIF4B has one SUMO-interacting motif (SIM) between the amino acid position 166 and 170 (166IRVDV170), which mediates the association between eIF4B and RSK1 through SUMO-SIM interaction. These results indicate that SUMOylation regulates the phosphorylation of RSK1 downstream substrates, which is required for efficient KSHV lytic replication.

scholarly journals Beyond K48 and K63: non-canonical protein ubiquitination

2021 ◽  
Vol 26 (1) ◽  
Author(s):  
Michal Tracz ◽  
Wojciech Bialek
Keyword(s):  
Free Amino ◽  
The Other ◽  
Critical Element ◽  
Amino Group ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Protein Ubiquitination ◽  
N Terminus ◽  
Lysine Residues

AbstractProtein ubiquitination has become one of the most extensively studied post-translational modifications. Originally discovered as a critical element in highly regulated proteolysis, ubiquitination is now regarded as essential for many other cellular processes. This results from the unique features of ubiquitin (Ub) and its ability to form various homo- and heterotypic linkage types involving one of the seven different lysine residues or the free amino group located at its N-terminus. While K48- and K63-linked chains are broadly covered in the literature, the other types of chains assembled through K6, K11, K27, K29, and K33 residues deserve equal attention in the light of the latest discoveries. Here, we provide a concise summary of recent advances in the field of these poorly understood Ub linkages and their possible roles in vivo.

scholarly journals Molecular Pathways Involved in the Development of Congenital Erythrocytosis

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1150
Author(s):  
Jana Tomc ◽  
Nataša Debeljak
Keyword(s):  
Signal Transduction ◽  
Iron Homeostasis ◽  
Molecular Mechanisms ◽  
Oxygen Affinity ◽  
Molecular Pathways ◽  
Disease Development ◽  
Post Translational Modifications ◽  
Hemoglobin Oxygen Affinity ◽  
Insight Into ◽  
Idiopathic Erythrocytosis

Patients with idiopathic erythrocytosis are directed to targeted genetic testing including nine genes involved in oxygen sensing pathway in kidneys, erythropoietin signal transduction in pre-erythrocytes and hemoglobin-oxygen affinity regulation in mature erythrocytes. However, in more than 60% of cases the genetic cause remains undiagnosed, suggesting that other genes and mechanisms must be involved in the disease development. This review aims to explore additional molecular mechanisms in recognized erythrocytosis pathways and propose new pathways associated with this rare hematological disorder. For this purpose, a comprehensive review of the literature was performed and different in silico tools were used. We identified genes involved in several mechanisms and molecular pathways, including mRNA transcriptional regulation, post-translational modifications, membrane transport, regulation of signal transduction, glucose metabolism and iron homeostasis, which have the potential to influence the main erythrocytosis-associated pathways. We provide valuable theoretical information for deeper insight into possible mechanisms of disease development. This information can be also helpful to improve the current diagnostic solutions for patients with idiopathic erythrocytosis.

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