scholarly journals A novel role of Zebrafish TMEM33 in negative regulation of interferon production by two distinct mechanisms

2021 ◽  
Vol 17 (2) ◽  
pp. e1009317
Author(s):  
Long-Feng Lu ◽  
Can Zhang ◽  
Zhuo-Cong Li ◽  
Xiao-Yu Zhou ◽  
Jing-Yu Jiang ◽  
...  
Keyword(s):  
Transmembrane Domain ◽  
Transmembrane Protein ◽  
Mrna Level ◽  
Negative Regulator ◽  
Functional Domain ◽  
Mitochondrial Antiviral Signaling ◽  
Viral Components ◽  
Insight Into ◽  
Zebrafish Liver

The transmembrane protein 33 (TMEM33) was originally identified as an endoplasmic reticulum (ER) protein that influences the tubular structure of the ER and modulates intracellular calcium homeostasis. However, the role of TMEM33 in antiviral immunity in vertebrates has not been elucidated. In this article, we demonstrate that zebrafish TMEM33 is a negative regulator of virus-triggered interferon (IFN) induction via two mechanisms: mitochondrial antiviral signaling protein (MAVS) ubiquitination and a decrease in the kinase activity of TANK binding kinase 1 (TBK1). Upon stimulation with viral components, tmem33 was remarkably upregulated in the zebrafish liver cell line. The IFNφ1 promoter (IFNφ1pro) activity and mRNA level induced by retinoic acid-inducible gene (RIG)-I-like receptors (RLRs) were significantly inhibited by TMEM33. Knockdown of TMEM33 increased host ifn transcription. Subsequently, we found that TMEM33 was colocalized in the ER and interacted with the RLR cascades, whereas MAVS was degraded by TMEM33 during the K48-linked ubiquitination. On the other hand, TMEM33 reduced the phosphorylation of mediator of IFN regulatory factor 3 (IRF3) activation (MITA)/IRF3 by acting as a decoy substrate of TBK1, which was also phosphorylated. A functional domain assay revealed that the N-terminal transmembrane domain 1 (TM1) and TM2 regions of TMEM33 were necessary for IFN suppression. Finally, TMEM33 significantly attenuated the host cellular antiviral capacity by blocking the IFN response. Taken together, our findings provide insight into the different mechanisms employed by TMEM33 in cellular IFN-mediated antiviral process.

scholarly journals Molecular Basis for CCRL2 Regulation of Leukocyte Migration

2020 ◽  
Vol 8 ◽  
Author(s):  
Tiziana Schioppa ◽  
Francesca Sozio ◽  
Ilaria Barbazza ◽  
Sara Scutera ◽  
Daniela Bosisio ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Chemokine Receptors ◽  
Transmembrane Domain ◽  
Nk Cell ◽  
Structural Features ◽  
Negative Regulator ◽  
Leukocyte Migration ◽  
Genetic Ablation

CCRL2 is a seven-transmembrane domain receptor that belongs to the chemokine receptor family. At difference from other members of this family, CCRL2 does not promote chemotaxis and shares structural features with atypical chemokine receptors (ACKRs). However, CCRL2 also differs from ACKRs since it does not bind chemokines and is devoid of scavenging functions. The only commonly recognized CCRL2 ligand is chemerin, a non-chemokine chemotactic protein. CCRL2 is expressed both by leukocytes and non-hematopoietic cells. The genetic ablation of CCRL2 has been instrumental to elucidate the role of this receptor as positive or negative regulator of inflammation. CCRL2 modulates leukocyte migration by two main mechanisms. First, when CCRL2 is expressed by barrier cells, such endothelial, and epithelial cells, it acts as a presenting molecule, contributing to the formation of a non-soluble chemotactic gradient for leukocytes expressing CMKLR1, the functional chemerin receptor. This mechanism was shown to be crucial in the induction of NK cell-dependent immune surveillance in lung cancer progression and metastasis. Second, by forming heterocomplexes with other chemokine receptors. For instance, CCRL2/CXCR2 heterodimers were shown to regulate the activation of β2-integrins in mouse neutrophils. This mini-review summarizes the current understanding of CCRL2 biology, based on experimental evidence obtained by the genetic deletion of this receptor in in vivo experimental models. Further studies are required to highlight the complex functional role of CCRL2 in different organs and pathological conditions.

scholarly journals Structure of an atypical FeoB G-domain reveals a putative domain-swapped dimer

2013 ◽  
Vol 69 (4) ◽  
pp. 399-404 ◽  
Author(s):  
Chandrika N. Deshpande ◽  
Aaron P. McGrath ◽  
Josep Font ◽  
Amy P. Guilfoyle ◽  
Megan J. Maher ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Ferrous Iron ◽  
Iron Uptake ◽  
Transmembrane Domain ◽  
Transmembrane Protein ◽  
Gtpase Domain ◽  
Helical Domain ◽  
Precise Role ◽  
Putative Domain

FeoB is a transmembrane protein involved in ferrous iron uptake in prokaryotic organisms. FeoB comprises a cytoplasmic soluble domain termed NFeoB and a C-terminal polytopic transmembrane domain. Recent structures of NFeoB have revealed two structural subdomains: a canonical GTPase domain and a five-helix helical domain. The GTPase domain hydrolyses GTP to GDP through a well characterized mechanism, a process which is required for Fe2+transport. In contrast, the precise role of the helical domain has not yet been fully determined. Here, the structure of the cytoplasmic domain of FeoB fromGallionella capsiferriformansis reported. Unlike recent structures of NFeoB, theG. capsiferriformansNFeoB structure is highly unusual in that it does not contain a helical domain. The crystal structures of both apo and GDP-bound protein forms a domain-swapped dimer.

scholarly journals The Interferon Stimulator Mitochondrial Antiviral Signaling Protein Facilitates Cell Death by Disrupting the Mitochondrial Membrane Potential and by Activating Caspases

2009 ◽  
Vol 84 (5) ◽  
pp. 2421-2431 ◽  
Author(s):  
Chia-Yi Yu ◽  
Ruei-Lin Chiang ◽  
Tsung-Hsien Chang ◽  
Ching-Len Liao ◽  
Yi-Ling Lin
Keyword(s):  
Cell Death ◽  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Caspase Cleavage ◽  
Infected Cells ◽  
Mitochondrial Antiviral Signaling ◽  
Antiviral Innate Immunity ◽  
Viral Components

ABSTRACT Interferon (IFN) signaling is initiated by the recognition of viral components by host pattern recognition receptors. Dengue virus (DEN) triggers IFN-β induction through a molecular mechanism involving the cellular RIG-I/MAVS signaling pathway. Here we report that the MAVS protein level is reduced in DEN-infected cells and that caspase-1 and caspase-3 cleave MAVS at residue D429. In addition to its well-known function in IFN induction, MAVS is also a proapoptotic molecule that triggers disruption of the mitochondrial membrane potential and activation of caspases. Although different domains are required for the induction of cytotoxicity and IFN, caspase cleavage at residue 429 abolished both functions of MAVS. The apoptotic role of MAVS in viral infection and double-stranded RNA (dsRNA) stimulation was demonstrated in cells with reduced endogenous MAVS expression induced by RNA interference. Even though IFN-β promoter activation was largely suppressed, DEN production was not affected greatly in MAVS knockdown cells. Instead, DEN- and dsRNA-induced cell death and caspase activation were delayed and attenuated in the cells with reduced levels of MAVS. These results reveal a new role of MAVS in the regulation of cell death beyond its well-known function of IFN induction in antiviral innate immunity.

Age-dependent regulation of vasopressin V1a receptors in preglomerular vessels from the spontaneously hypertensive rat

2004 ◽  
Vol 286 (5) ◽  
pp. F997-F1003 ◽  
Author(s):  
Øyvind B. Vågnes ◽  
Frank H. Hansen ◽  
Rolf E. F. Christiansen ◽  
Camilla Gjerstad ◽  
Bjarne M. Iversen
Keyword(s):  
Spontaneously Hypertensive Rat ◽  
Mrna Level ◽  
Cytosolic Calcium ◽  
Receptor Expression ◽  
Receptor Protein ◽  
Spontaneously Hypertensive ◽  
Wistar Kyoto ◽  
Renal Vascular ◽  
Insight Into

Experiments were performed to get insight into the role of AVP receptor V1a regulation with age, i.e., during development and maintenance of high blood pressure. Previous studies showed an increased gene expression and renal vascular response to AVP in young spontaneously hypertensive rats (SHR). The age regulation of the V1a receptor was examined in preglomerular vessels from 5-, 10-, 20-, and 70-wk-old SHR using normotensive Wistar-Kyoto rats (WKY) as controls. Real-time PCR and ligand binding were used for analysis of receptor expression, and the change in cytosolic calcium concentration during stimulation of isolated preglomerular vessels with AVP was studied. Studies showed an increase of the V1a receptor protein and mRNA from 5-and 10-wk-old SHR compared with vessels from 20- and 70-wk-old SHR. In 5-wk-old SHR receptor density was 84 ± 13 fmol/mg protein, and 38 ± 11 fmol/mg protein in 70-wk-old SHR ( P < 0.05). mRNA in the 5- and 70-wk-old SHR was 15,854 ± 629 and 3,181 ± 224 V1a mRNA/108 18S ribosomal RNA, respectively ( P < 0.001). Values from WKY at all ages were similar to 20- and 70-wk-old SHR. During stimulation with AVP, the change in cytosolic calcium in vessels from 5-wk-old SHR increased 234 ± 59 nM, whereas the increase was 89 ± 9 nM in 70-wk-old SHR ( P = 0.03). These results indicate that the V1a receptor is increased at protein and mRNA level during development of hypertension in SHR but is normalized when hypertension is established.

scholarly journals Cryo-EM structures of human TMEM120A and TMEM120B

2021 ◽  
Author(s):  
Meng Ke ◽  
Yue Yu ◽  
Changjian Zhao ◽  
Shirong Lai ◽  
Qiang Su ◽  
...  
Keyword(s):  
Potential Role ◽  
Transmembrane Domain ◽  
Transmembrane Protein ◽  
Expression System ◽  
Coiled Coil ◽  
Fatty Acid Elongase ◽  
Coiled Coil Domain ◽  
Induced Currents ◽  
The Difference

TMEM120A (Transmembrane protein 120A) was recently identified as a mechanical pain sensing ion channel named as TACAN, while its homologue TMEM120B has no mechanosensing property1. Here, we report the cryo-EM structures of both human TMEM120A and TMEM120B. The two structures share the same dimeric assembly, mediated by extensive interactions through the transmembrane domain (TMD) and the N-terminal coiled coil domain (CCD). However, the nearly identical structures cannot provide clues for the difference in mechanosensing between TMEM120A and TMEM120B. Although TMEM120A could mediate conducting currents in a bilayer system, it does not mediate mechanical-induced currents in a heterologous expression system, suggesting TMEM120A is unlikely a mechanosensing channel. Instead, the TMDs of TMEM120A and TMEM120B resemble the structure of a fatty acid elongase, ELOVL7, indicating their potential role of an enzyme in lipid metabolism.

scholarly journals Differential roles of RIG-I like receptors in SARS-CoV-2 infection

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Duo-Meng Yang ◽  
Ting-Ting Geng ◽  
Andrew G. Harrison ◽  
Peng-Hua Wang
Keyword(s):  
Epithelial Cells ◽  
Mrna Level ◽  
Type I ◽  
Angiotensin Converting Enzyme 2 ◽  
Mitochondrial Antiviral Signaling ◽  
Entry Receptor ◽  
Mitochondrial Antiviral Signaling Protein ◽  
Initial Target ◽  
Inducible Gene

AbstractRetinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5) sense viral RNA and activate antiviral immune responses. Herein we investigate their functions in human epithelial cells, the primary and initial target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A deficiency in MDA5, RIG-I or mitochondrial antiviral signaling protein (MAVS) enhanced viral replication. The expression of the type I/III interferon (IFN) during infection was impaired in MDA5−/− and MAVS−/−, but not in RIG-I−/−, when compared to wild type (WT) cells. The mRNA level of full-length angiotensin-converting enzyme 2 (ACE2), the cellular entry receptor for SARS-CoV-2, was ~ 2.5-fold higher in RIG-I−/− than WT cells. These data demonstrate MDA5 as the predominant SARS-CoV-2 sensor, IFN-independent induction of ACE2 and anti-SARS-CoV-2 role of RIG-I in epithelial cells.

A comprehensive overview of PPM1A: From structure to disease

2021 ◽  
pp. 153537022110618
Author(s):  
Mao Li ◽  
Xingfeng Xu ◽  
Yan Su ◽  
Xiaoyun Shao ◽  
Yali Zhou ◽  
...  
Keyword(s):  
Negative Regulator ◽  
Comprehensive Overview ◽  
Physiological Processes ◽  
Stress Response Pathway ◽  
Family Protein ◽  
Wide Range ◽  
Proliferation And Apoptosis ◽  
Insight Into ◽  
Phosphate Groups

PPM1A (magnesium-dependent phosphatase 1 A, also known as PP2Cα) is a member of the Ser/Thr protein phosphatase family. Protein phosphatases catalyze the removal of phosphate groups from proteins via hydrolysis, thus opposing the role of protein kinases. The PP2C family is generally considered a negative regulator in the eukaryotic stress response pathway. PPM1A can bind and dephosphorylate various proteins and is therefore involved in the regulation of a wide range of physiological processes. It plays a crucial role in transcriptional regulation, cell proliferation, and apoptosis and has been suggested to be closely related to the occurrence and development of cancers of the lung, bladder, and breast, amongst others. Moreover, it is closely related to certain autoimmune diseases and neurodegenerative diseases. In this review, we provide an insight into currently available knowledge of PPM1A, including its structure, biological function, involvement in signaling pathways, and association with diseases. Lastly, we discuss whether PPM1A could be targeted for therapy of certain human conditions.

scholarly journals Drosophila Rab39 Attenuates Lysosomal Degradation

2021 ◽  
Vol 22 (19) ◽  
pp. 10635
Author(s):  
Zsolt Lakatos ◽  
Péter Benkő ◽  
Gábor Juhász ◽  
Péter Lőrincz
Keyword(s):  
De Novo ◽  
Fat Body ◽  
Small Gtpases ◽  
Negative Regulator ◽  
Valuable Insight ◽  
Biological Mechanisms ◽  
Lysosomal Degradation ◽  
The Common ◽  
Insight Into

Lysosomal degradation, the common destination of autophagy and endocytosis, is one of the most important elements of eukaryotic metabolism. The small GTPases Rab39A and B are potential new effectors of this pathway, as their malfunction is implicated in severe human diseases like cancer and neurodegeneration. In this study, the lysosomal regulatory role of the single Drosophila Rab39 ortholog was characterized, providing valuable insight into the potential cell biological mechanisms mediated by these proteins. Using a de novo CRISPR-generated rab39 mutant, we found no failure in the early steps of endocytosis and autophagy. On the contrary, we found that Rab39 mutant nephrocytes internalize and degrade endocytic cargo at a higher rate compared to control cells. In addition, Rab39 mutant fat body cells contain small yet functional autolysosomes without lysosomal fusion defect. Our data identify Drosophila Rab39 as a negative regulator of lysosomal clearance during both endocytosis and autophagy.

scholarly journals Proteomic Analysis of NRROS Interactome Reveals the Presence of Chaperones and Mediators of the ERAD Pathway

2018 ◽  
Author(s):  
Rajkumar Noubade ◽  
Qui Phung ◽  
Wilson Phung ◽  
Erik Verschueren ◽  
Laura Lau ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Transmembrane Protein ◽  
Protein Biosynthesis ◽  
Reactive Oxygen ◽  
Negative Regulator ◽  
Spectrometric Analysis ◽  
Functional Domain ◽  
Oxygen Species ◽  
Er Quality Control ◽  
Erad Pathway

AbstractNegative regulator of reactive oxygen species (NRROS, previously called LRRC33) is a leucine-rich repeat (LRR) domain containing, ER-resident transmembrane protein expressed primarily in lymphoid organs, especially in myeloid cells. We have previously demonstrated that NRROS regulates reactive oxygen species production by phagocytic cells by mediating degradation of NOX2 (gp91phox), a component of NOX2 complex responsible for the oxidative burst in these cells. Since LRR is the only functional domain in NRROS, it is likely to interact with other proteins for its biological functions. Here, by performing immunoprecipitation of NRROS and mass spectrometric analysis, we describe the NRROS interactome in macrophages and demonstrate that NRROS interacts with molecular chaperones/co-chaperones and mediators of the endoplasmic reticulum associated degradation (ERAD) pathway such as calnexin, suggesting a broader role for NRROS in protein biosynthesis and the ER quality control machinery.

scholarly journals Whole genome resequencing reveals an association of ABCC4 variants with preaxial polydactyly in pigs

2020 ◽  
Author(s):  
Cheng Ma ◽  
Saber Khederzadeh ◽  
Adeniyi C. Adeola ◽  
Xu-Man Han ◽  
Hai-Bing Xie ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Transmembrane Domain ◽  
Transmembrane Protein ◽  
Strong Association ◽  
Genetic Variations ◽  
Preaxial Polydactyly ◽  
Normal Individuals ◽  
Congenital Limb ◽  
Whole Genome Resequencing

Abstract Background: Polydactyly is one of the most common congenital limb dysplasia in many animal species. Although preaxial polydactyly (PPD) has been comprehensively studied in humans as a common abnormality, the genetic variations in other animals have not been fully understood. Herein, we focused on the pig, as an even-toed ungulate mammal model with its unique advantages in medical and genetic researches, two PPD families consisting of four affected and 20 normal individuals were sequenced. Results: Our results showed that the PPD in the sampled pigs were not related to the variants reported in earlier studies. A strong association was identified at ABCC4 and it encodes a transmembrane protein involved in ciliogenesis. We found that the affected and normal individuals were highly differentiated at ABCC4, and all the PPD individuals shared long haplotype stretches as compared with the unaffected individuals. A highly differentiated missense mutation (I85T) in ABCC4 was observed at a residue from a transmembrane domain highly conserved among a variety of organisms. Conclusions: This study reports ABCC4 as a new candidate gene for PPD in pigs and identifies a missense mutation. Our results illustrate a putative role of ciliogenesis process in PPD, coinciding with an earlier observation of ciliogenesis abnormality resulting in pseudo-thumb development in pandas. These results expand our knowledge on the genetic variations underlying PPD in animals.

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