scholarly journals Viperin catalyzes methionine oxidation to promote protein expression and function of helicases

2019 ◽  
Vol 5 (8) ◽  
pp. eaax1031 ◽  
Author(s):  
Lei Bai ◽  
Jiazhen Dong ◽  
Zhenqiu Liu ◽  
Youliang Rao ◽  
Pinghui Feng ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Methionine Oxidation ◽  
Biological Processes ◽  
Loss Of Function ◽  
Rna Helicases ◽  
Dna And Rna ◽  
Biochemical Studies ◽  
The Stability ◽  
And Function

Helicases play pivotal roles in fundamental biological processes, and posttranslational modifications regulate the localization, function, and stability of helicases. Here, we report that methionine oxidation of representative helicases, including DNA and RNA helicases of viral (ORF44 of KSHV) and cellular (MCM7 and RIG-I) origin, promotes their expression and functions. Cellular viperin, a major antiviral interferon-stimulated gene whose functions beyond host defense remain largely unknown, catalyzes the methionine oxidation of these helicases. Moreover, biochemical studies entailing loss-of-function mutations of helicases and a pharmacological inhibitor interfering with lipid metabolism and, hence, decreasing viperin activity indicate that methionine oxidation potently increases the stability and enzyme activity of these helicases that are critical for DNA replication and immune activation. Our work uncovers a pivotal role of viperin in catalyzing the methionine oxidation of helicases that are implicated in diverse fundamental biological processes.

scholarly journals Prediction of Functional Consequences of Missense Mutations in ANO4 Gene

2021 ◽  
Vol 22 (5) ◽  
pp. 2732
Author(s):  
Nadine Reichhart ◽  
Vladimir M. Milenkovic ◽  
Christian H. Wetzel ◽  
Olaf Strauß
Keyword(s):  
Transmembrane Protein ◽  
Functional Characterization ◽  
Missense Mutations ◽  
Mutant Proteins ◽  
Functional Consequences ◽  
New Perspective ◽  
The Stability ◽  
Dynamics Simulations ◽  
And Function

The anoctamin (TMEM16) family of transmembrane protein consists of ten members in vertebrates, which act as Ca2+-dependent ion channels and/or Ca2+-dependent scramblases. ANO4 which is primarily expressed in the CNS and certain endocrine glands, has been associated with various neuronal disorders. Therefore, we focused our study on prioritizing missense mutations that are assumed to alter the structure and stability of ANO4 protein. We employed a wide array of evolution and structure based in silico prediction methods to identify potentially deleterious missense mutations in the ANO4 gene. Identified pathogenic mutations were then mapped to the modeled human ANO4 structure and the effects of missense mutations were studied on the atomic level using molecular dynamics simulations. Our data show that the G80A and A500T mutations significantly alter the stability of the mutant proteins, thus providing new perspective on the role of missense mutations in ANO4 gene. Results obtained in this study may help to identify disease associated mutations which affect ANO4 protein structure and function and might facilitate future functional characterization of ANO4.

scholarly journals Thioester-Containing Protein-4 Regulates the Drosophila Immune Signaling and Function against the Pathogen Photorhabdus

2016 ◽  
Vol 9 (1) ◽  
pp. 83-93 ◽  
Author(s):  
Upasana Shokal ◽  
Ioannis Eleftherianos
Keyword(s):  
Immune Response ◽  
Photorhabdus Luminescens ◽  
Human Pathogen ◽  
Loss Of Function ◽  
Phenoloxidase Activity ◽  
Microbial Infections ◽  
Immune Pathways ◽  
And Function ◽  
Important Progress

Despite important progress in identifying the molecules that participate in the immune response of Drosophila melanogaster to microbial infections, the involvement of thioester-containing proteins (TEPs) in the antibacterial immunity of the fly is not fully clarified. Previous studies mostly focused on identifying the function of TEP2, TEP3 and TEP6 molecules in the D. melanogaster immune system. Here, we investigated the role of TEP4 in the regulation and function of D. melanogaster host defense against 2 virulent pathogens from the genus Photorhabdus, i.e. the insect pathogenic bacterium Photorhabdus luminescens and the emerging human pathogen P. asymbiotica. We demonstrate that Tep4 is strongly upregulated in adult flies following the injection of Photorhabdus bacteria. We also show that Tep4 loss-of-function mutants are resistant to P. luminescens but not to P. asymbiotica infection. In addition, we find that inactivation of Tep4 results in the upregulation of the Toll and Imd immune pathways, and the downregulation of the Jak/Stat and Jnk pathways upon Photorhabdus infection. We document that loss of Tep4 promotes melanization and phenoloxidase activity in the mutant flies infected with Photorhabdus. Together, these findings generate novel insights into the immune role of TEP4 as a regulator and effector of the D. melanogaster antibacterial immune response.

PIN-FORMED 1 regulates cell fate at the periphery of the shoot apical meristem

Development ◽  
2000 ◽  
Vol 127 (23) ◽  
pp. 5157-5165 ◽  
Author(s):  
T. Vernoux ◽  
J. Kronenberger ◽  
O. Grandjean ◽  
P. Laufs ◽  
J. Traas
Keyword(s):  
Cell Fate ◽  
Apical Meristem ◽  
Transmembrane Protein ◽  
Loss Of Function ◽  
Hybrid Identity ◽  
Hormone Transport ◽  
Early Markers ◽  
Ideal Tool ◽  
And Function

The process of organ positioning has been addressed, using the pin-formed 1 (pin1) mutant as a tool. PIN1 is a transmembrane protein involved in auxin transport in Arabidopsis. Loss of function severely affects organ initiation, and pin1 mutants are characterised by an inflorescence meristem that does not initiate any flowers, resulting in the formation of a naked inflorescence stem. This phenotype, combined with the proposed role of PIN1 in hormone transport, makes the mutant an ideal tool to study organ formation and phyllotaxis, and here we present a detailed analysis of the molecular modifications at the shoot apex caused by the mutation. We show that meristem structure and function are not severely affected in the mutant. Major alterations, however, are observed at the periphery of the pin1 meristem, where organ initiation should occur. Although two very early markers of organ initiation, LEAFY and AINTEGUMENTA, are expressed at the periphery of the mutant meristem, the cells are not recruited into distinct primordia. Instead a ring-like domain expressing those primordium specific genes is observed around the meristem. This ring-like domain also expresses a boundary marker, CUP-SHAPED COTYLEDON 2, involved in organ separation, showing that the zone at the meristem periphery has a hybrid identity. This implies that PIN1 is not only involved in organ outgrowth, but that it is also necessary for organ separation and positioning. A model is presented in which PIN1 and the local distribution of auxin control phyllotaxis.

scholarly journals The role of micro-RNAs in the female reproductive tract

Reproduction ◽  
2012 ◽  
Vol 143 (5) ◽  
pp. 559-576 ◽  
Author(s):  
Warren B Nothnick
Keyword(s):  
Posttranslational Modifications ◽  
Reproductive Tract ◽  
Current Knowledge ◽  
Female Reproductive Tract ◽  
Micro Rna ◽  
Proper Function ◽  
Posttranscriptional Gene Regulation ◽  
Micro Rnas ◽  
And Function

Proper development and function of the female reproductive tract are essential for successful reproduction. Regulation of the differentiated functions of the organs that make up the female reproductive tract is well established to occur at multiple levels including transcription, translation, and posttranslational modifications. Micro-RNA (miRNA)-mediated posttranscriptional gene regulation has emerged as a fundamental mechanism controlling normal tissue development and function. Emerging evidence indicates that miRNAs are expressed within the organs of the female reproductive tract where they function to regulate cellular pathways necessary for proper function of these organs. In this review, the functional significance of miRNAs in the development and function of the organs of the female reproductive tract is discussed. Initial discussion focuses on the role of miRNAs in the development of the organs of the female reproductive tract highlighting recent studies that clearly demonstrate that mice with disrupted Dicer1 expression are sterile, fail to develop uterine glands, and have muted estrogen responsiveness. Next, emphasis moves to discussion on our current knowledge on the characterization of miRNA expression in each of the organs of the female reproductive tract. When possible, information is presented and discussed with respect to regulation, function, and/or functional targets of these miRNA within each specific organ of the female reproductive tract.

scholarly journals The Role of Phosphotyrosine Signaling Pathway in Parotid Gland Proliferation and Function

1995 ◽  
Vol 6 (2) ◽  
pp. 119-131 ◽  
Author(s):  
K.R. Purushotham ◽  
M.G. Humphreys-Beher
Keyword(s):  
Salivary Glands ◽  
Tyrosine Kinases ◽  
Intracellular Signaling ◽  
Potential Role ◽  
Biological Processes ◽  
Secretory Function ◽  
Phosphotyrosine Signaling ◽  
And Function ◽  
Active Proliferation

Tyrosine phosphorylation and the intracellular signaling processes associated with it have been the focus of intense study due to its importance in the regulation of biological processes as diverse as cell proliferation and cell differentiation. While much of what we now understand has been derived from the study of cell lines and tumor cells, the salivary glands provide a model to examine the effects of tyrosine kinases and tyrosine phosphatases in a normal differentiated tissue. This review will focus, therefore, on the role tyrosine kinases and phosphatases play in inducing the transition from stasis to active proliferation and their potential role in mediating secretory function of the salivary glands.

scholarly journals Hnrnpul1 loss of function affects skeletal and limb development

2020 ◽  
Author(s):  
Danielle L Blackwell ◽  
Sherri D Fraser ◽  
Oana Caluseriu ◽  
Claudia Vivori ◽  
Paul MK Gordon ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Limb Development ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Nucleic Acid Binding ◽  
Loss Of Function ◽  
Zebrafish Model ◽  
Dna And Rna ◽  
Developmental Role

AbstractMutations in RNA binding proteins can lead to pleiotropic phenotypes including craniofacial, skeletal, limb and neurological symptoms. Heterogeneous Nuclear Ribonucleoproteins (hnRNPs) are involved in nucleic acid binding, transcription and splicing through direct binding to DNA and RNA, or through interaction with other proteins in the spliceosome. Here, we show a developmental role for hnrnpul1 in zebrafish fin and craniofacial development, and in adult onset scoliosis. Furthermore, we demonstrate a role of hnrnpul1 in alternative splicing regulation. In two siblings with congenital limb malformations, whole exome sequencing detected a frameshift variant in HNRNPUL1; the developmental role of this gene in humans has not been explored. Our data suggest an important developmental role of hnRNPUL1 in both zebrafish and humans. Although there are differences in phenotypes between species, our data suggests potential conservation of ancient regulatory circuits involving hnRNPUL1 in these phylogenetically distant species.Summary statementA zebrafish model of loss of Hnrnpul1 shows alternative splicing defects and results in limb growth, craniofacial tendon, and skeletal anomalies.

scholarly journals A nanobody-based molecular toolkit provides new mechanistic insight into clathrin-coat initiation

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Linton M Traub
Keyword(s):  
Decisive Role ◽  
Subcellular Location ◽  
Combined Approach ◽  
Mechanistic Insight ◽  
Early Endosomes ◽  
The Stability ◽  
And Function ◽  
Insight Into ◽  
Complementarity Determining Region

Besides AP-2 and clathrin triskelia, clathrin coat inception depends on a group of early-arriving proteins including Fcho1/2 and Eps15/R. Using genome-edited cells, we described the role of the unstructured Fcho linker in stable AP-2 membrane deposition. Here, expanding this strategy in combination with a new set of llama nanobodies against EPS15 shows an FCHO1/2–EPS15/R partnership plays a decisive role in coat initiation. A nanobody containing an Asn-Pro-Phe peptide within the complementarity-determining region 3 loop is a function-blocking pseudoligand for tandem EPS15/R EH domains. Yet, in living cells, EH domains gathered at clathrin-coated structures are poorly accessible, indicating residence by endogenous NPF-bearing partners. Forcibly sequestering cytosolic EPS15 in genome-edited cells with nanobodies tethered to early endosomes or mitochondria changes the subcellular location and availability of EPS15. This combined approach has strong effects on clathrin coat structure and function by dictating the stability of AP-2 assemblies at the plasma membrane.

scholarly journals Fundamental Role Of The H2A.Z C-Terminal Tail In The Formation Of Constitutive Heterochromatin

2021 ◽  
Author(s):  
László Imre ◽  
Péter Nánási ◽  
Rosevalentine Bosire ◽  
Ágota Csóti ◽  
Kata Nóra Enyedi ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Constitutive Heterochromatin ◽  
Large Fraction ◽  
Gene Expression Pattern ◽  
Histone Variant ◽  
Unusual Behavior ◽  
Isoform Specificity ◽  
The Stability

ABSTRACTNucleosome stability, a crucial determinant of gene regulation, was measured in a robust in situ assay to assess the molecular determinants of the stability of H2A.Z-containig nucleosomes. Surprisingly, a large fraction of H2A.Z detected by three different antibodies was released from the nucleosomes by salt together with H3, and was associated with H3K9me3 but not with H3K27me3 marked nucleosomes. This unusual behavior relied on the presence of the unstructured C-terminal chain of the histone variant, rather than on isoform specificity, posttranslational modifications or binding of the reader protein PWWPA2, as determined using cell lines expressing only particular forms of the variant. In the absence of this tail, or upon addition of an excess of the tail peptide to the nuclei of control cells, the canonical H2A-like stability features were readily restored and most of the H2A.Z-containing nucleosomes left the periphery and ended up in scattered foci in the nuclei. Concomitantly, the H3K9me3-marked constitutive heterochromatin was also dispersed, what was accompanied by increased overall nuclease sensitivity and significantly enhanced binding of intercalating dyes to the DNA. The DT40 cells expressing the tailless H2A.Z showed marked differences in their gene expression pattern and were distinguished by compromised DNA damage response. Thus, interactions involving a short H2A.Z peptide chain simultaneously determine the stability and accessibility features of chromatin involving the nucleosomes containing this histone variant and the localization of these large chromatin regions in the nucleus. Our data suggest that H2A.Z can function in both heterochromatic and in euchromatic scenarios depending on the molecular interactions involving its C-terminal unstructured tail, shedding light on the enigmatic double-faced character of this histone variant.

Dietary and Physiological Effects of Zinc on the Immune System

2021 ◽  
Vol 41 (1) ◽  
Author(s):  
Inga Wessels ◽  
Henrike Josephine Fischer ◽  
Lothar Rink
Keyword(s):  
Immune Responses ◽  
Immune Cells ◽  
Immune Cell ◽  
Current Knowledge ◽  
Annual Review ◽  
Publication Date ◽  
Biological Processes ◽  
And Function ◽  
Broad Overview

Evidence for the importance of zinc for all immune cells and for mounting an efficient and balanced immune response to various environmental stressors has been accumulating in recent years. This article describes the role of zinc in fundamental biological processes and summarizes our current knowledge of zinc's effect on hematopoiesis, including differentiation into immune cell subtypes. In addition, the important role of zinc during activation and function of immune cells is detailed and associated with the specific immune responses to bacteria, parasites, and viruses. The association of zinc with autoimmune reactions and cancers as diseases with increased or decreased immune responses is also discussed. This article provides a broad overview of the manifold roles that zinc, or its deficiency, plays in physiology and during various diseases. Consequently, we discuss why zinc supplementation should be considered, especially for people at risk of deficiency. Expected final online publication date for the Annual Review of Nutrition, Volume 41 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals The Role of Packing Defects in the Stability and Function of the Intramembrane Protease GlpG

2017 ◽  
Vol 112 (3) ◽  
pp. 86a
Author(s):  
Ruiqiong Guo ◽  
Zixuan Cang ◽  
Deans Erin ◽  
Guowei Wei ◽  
Heedeok Hong
Keyword(s):  
Packing Defects ◽  
The Stability ◽  
And Function
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