A New Trick for an Old Dogma: ENaC Proteins as Mechanotransducers in Vascular Smooth Muscle

Physiology ◽  
2008 ◽  
Vol 23 (1) ◽  
pp. 23-31 ◽  
Author(s):  
Heather A. Drummond ◽  
Samira C. Grifoni ◽  
Nikki L. Jernigan
Keyword(s):  
Extracellular Matrix ◽  
Cytoskeletal Proteins ◽  
Protective Mechanism ◽  
C Elegans ◽  
Mechanical Signaling ◽  
Evolutionarily Conserved ◽  
Ion Conducting ◽  
New Perspective ◽  
Renal Blood Flow Autoregulation

Myogenic constriction is a vasoconstriction of blood vessels to increases in perfusion pressure. In renal preglomerular vasculature, it is an established mechanism of renal blood flow autoregulation. Recently, myogenic constriction has been identified as an important protective mechanism, preventing the transmission of systemic pressure to the fragile glomerular vasculature. Although the signal transduction pathways mediating vasoconstriction are well known, how the increases in pressure trigger vasoconstriction is unclear. The response is initiated by pressure-induced stretch of the vessel wall and thus is dependent on mechanical signaling. The identity of the sensor detecting VSMC stretch is unknown. Previous studies have considered the role of extracellular matrix-integrin interactions, ion conduction units (channels and/or transporters), and the cytoskeleton as pressure detectors. Whether, and how, these structures fit together in VSMCs is poorly understood. However, a model of mechanotransduction in the nematode Caenorhadbditis elegans ( C. elegans) has been established that ties together extracellular matrix, ion channels, and cytoskeletal proteins into a large mechanosensing complex. In the C. elegans mechanotransducer model, a family of evolutionarily conserved proteins, referred to as the DEG/ENaC/ASIC family, form the ion-conducting pore of the mechanotransducer. Members of this protein family are expressed in VSMC where they may participate in pressure detection. This review will address how the C. elegans mechanotransducer model can be used to model pressure detection in mammalian VSMCs and provide a new perspective to pressure detection in VSMCs.

scholarly journals WDR31 is a novel ciliopathy protein displaying functional redundancy with GTPase-activating proteins ELMOD and RP2 in recruiting BBSome to cilium

2021 ◽  
Author(s):  
Sebiha Cevik ◽  
Lama Alabdi ◽  
Xiaoyu Peng ◽  
Tina Beyer ◽  
Atiyye Zorluer ◽  
...  
Keyword(s):  
Clinical Features ◽  
Renal Agenesis ◽  
Rare Disorders ◽  
Compartment Analysis ◽  
C Elegans ◽  
Gtpase Activating Proteins ◽  
Mechanistic Analysis ◽  
Evolutionarily Conserved ◽  
Null Mutants

Abstract The term “ciliopathy” refers to a group of over 35 rare disorders characterized by defective cilia and many overlapping clinical features, such as hydrocephalus, cerebellar vermis hypoplasia, polydactyly, and retinopathy. Even though many genes have been implicated in ciliopathies, the genetic pathogenesis in certain cases remains still undisclosed. Here, we identified a homozygous truncating variant in WDR31 in a patient with a typical ciliopathy phenotype encompassing congenital hydrocephalus, polydactyly, and renal agenesis. WDR31 is an evolutionarily conserved protein that localizes to the cilium and cilia-related compartment. Analysis from zebrafish supports the role of WDR31 in regulating the cilia morphology. The CRISPR/Cas9 knock-in (p.Arg261del) C. elegans model of the patient variant (p.Arg268*) reproduced several cilia-related defects observed in wdr-31 null mutants. Mechanistic analysis from C. elegans revealed that WDR-31 functions redundantly with ELDM-1 (ELMOD protein) and RPI-2 (RP2) to regulate the IFT trafficking through controlling the cilia entry of the BBSome. This work revealed WDR31 as a new ciliopathy protein that regulates IFT and BBSome trafficking.

scholarly journals Molecular mechanisms of genetic damages of the myocardium in cardiomyopathy

2010 ◽  
Vol 56 (3) ◽  
pp. 319-328
Author(s):  
A.G. Hasanov ◽  
T.V. Bershova ◽  
E.N. Basargina ◽  
M.I. Bakanov
Keyword(s):  
Extracellular Matrix ◽  
Molecular Mechanisms ◽  
Genetic Factors ◽  
Cytoskeletal Proteins ◽  
Matrix Proteins ◽  
Force Generation ◽  
Cardiac Cell ◽  
Cell Dysfunction ◽  
Thick Filaments

The review highlighted problems of reorganization of myocardical contractile and cytoskeletal proteins in cardiomyopathy (CM). The role of the genetic factors coding contractile proteins, proteins of thin and thick filaments, and also extracellular matrix proteins in processes of formation and development of hypertrophic (HCM) and dilated (DCM) cardiomyopathy are analyzed. The mechanisms responsible for the changes in cardiac proteins on regulation involved into force generation, its transfer, recycling ATP, impairments in transmembranal signals, that finally lead to cardiac cell dysfunction determining various manifestations of CM are considered.

scholarly journals Phosphorylation of the microtubule-severing AAA+ enzyme Katanin regulates C. elegans embryo development

2020 ◽  
Vol 219 (6) ◽  
Author(s):  
Nicolas Joly ◽  
Eva Beaumale ◽  
Lucie Van Hove ◽  
Lisa Martino ◽  
Lionel Pintard
Keyword(s):  
Mitotic Spindle ◽  
The Other ◽  
Meiotic Spindle ◽  
Aaa Atpase ◽  
C Elegans ◽  
Microtubule Severing ◽  
Evolutionarily Conserved ◽  
Necessary And Sufficient ◽  
Fine Tune

The evolutionarily conserved microtubule (MT)-severing AAA-ATPase enzyme Katanin is emerging as a critical regulator of MT dynamics. In Caenorhabditis elegans, Katanin MT-severing activity is essential for meiotic spindle assembly but is toxic for the mitotic spindle. Here we analyzed Katanin dynamics in C. elegans and deciphered the role of Katanin phosphorylation in the regulation of its activity and stability. Katanin is abundant in oocytes, and its levels drop after meiosis, but unexpectedly, a significant fraction is present throughout embryogenesis, where it is dynamically recruited to the centrosomes and chromosomes during mitosis. We show that the minibrain kinase MBK-2, which is activated during meiosis, phosphorylates Katanin at multiple serines. We demonstrate unequivocally that Katanin phosphorylation at a single residue is necessary and sufficient to target Katanin for proteasomal degradation after meiosis, whereas phosphorylation at the other sites only inhibits Katanin ATPase activity stimulated by MTs. Our findings suggest that cycles of phosphorylation and dephosphorylation fine-tune Katanin level and activity to deliver the appropriate MT-severing activity during development.

scholarly journals Autophagy in Alcohol-Induced Multiorgan Injury: Mechanisms and Potential Therapeutic Targets

2014 ◽  
Vol 2014 ◽  
pp. 1-20 ◽  
Author(s):  
Yuan Li ◽  
Shaogui Wang ◽  
Hong-Min Ni ◽  
Heqing Huang ◽  
Wen-Xing Ding
Keyword(s):  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Current Knowledge ◽  
Therapeutic Targets ◽  
Degradation Pathway ◽  
Protective Mechanism ◽  
Intracellular Degradation ◽  
Injury Mechanisms ◽  
Evolutionarily Conserved

Autophagy is a genetically programmed, evolutionarily conserved intracellular degradation pathway involved in the trafficking of long-lived proteins and cellular organelles to the lysosome for degradation to maintain cellular homeostasis. Alcohol consumption leads to injury in various tissues and organs including liver, pancreas, heart, brain, and muscle. Emerging evidence suggests that autophagy is involved in alcohol-induced tissue injury. Autophagy serves as a cellular protective mechanism against alcohol-induced tissue injury in most tissues but could be detrimental in heart and muscle. This review summarizes current knowledge about the role of autophagy in alcohol-induced injury in different tissues/organs and its potential molecular mechanisms as well as possible therapeutic targets based on modulation of autophagy.

scholarly journals Evolutionarily conserved roles of Caenorhabditis elegans perilipin in lipolysis

2019 ◽  
Author(s):  
Filip Kaššák ◽  
Ahmed A Chughtai ◽  
Marta Kostrouchová
Keyword(s):  
Neutral Lipids ◽  
Physiological Role ◽  
Hormone Sensitive Lipase ◽  
Functional Connection ◽  
Regulatory Pathways ◽  
C Elegans ◽  
Evolutionarily Conserved ◽  
Eukaryotic Organisms

Neutral lipids and namely triacyl-glycerols (TAGs) are the prevalent excess energy storage molecules in all eukaryotic organisms. They are universally organized in active cytoplasmic organelles called lipid droplets (LDs) and their breakdown is performed and regulated in an evolutionarily conserved manner. In mammals, two distinct but inter-connected pathways are believed to mediate this catabolism: conventional cytoplasmic lipolysis with effector neutral lipases; and lipophagy, a specific kind of autophagy exploiting lysosomal acidic lipases. Central molecules in this regulation are LD-resident proteins, perilipins (PLINs). Our recent discovery of a sole PLIN orthologue in C. elegans offers a unique opportunity to study these regulatory pathways, provided that the interactive mechanisms are orthologous. To determine this, we employed classical genetics with genome editing tools and in vivo microscopy to provide three lines of evidence demonstrating the conserved role of the C. elegans perilipin. Firstly, we proved the common presence of a standard lipolytic apparatus on LDs. Next, we ascertained a functional connection between nematode PLIN-1 and the effector enzyme, hormone-sensitive lipase (HOSL-1). Finally, we identified lipophagy as a secondary lipolytic pathway, which is consistent with the mammalian model. Our data provide not only a proof of concept but also suggests interesting implications by questioning the physiological role of lipophagy in lipolysis.

scholarly journals WDR31 is a novel ciliopathy protein displaying functional redundancy with GTPase-activating proteins ELMOD and RP2 in recruiting BBSome to cilium

2021 ◽  
Author(s):  
Sebiha Cevik ◽  
Lama Alabdi ◽  
Xiaoyu Peng ◽  
Tina Beyer ◽  
Atiyye Zorluer ◽  
...  
Keyword(s):  
Clinical Features ◽  
Renal Agenesis ◽  
Rare Disorders ◽  
Compartment Analysis ◽  
C Elegans ◽  
Gtpase Activating Proteins ◽  
Mechanistic Analysis ◽  
Evolutionarily Conserved ◽  
Null Mutants

The term ciliopathy refers to a group of over 35 rare disorders characterized by defective cilia and many overlapping clinical features, such as hydrocephalus, cerebellar vermis hypoplasia, polydactyly, and retinopathy. Even though many genes have been implicated in ciliopathies, the genetic pathogenesis in certain cases remains still undisclosed. Here, we identified a homozygous truncating variant in WDR31 in a patient with a typical ciliopathy phenotype encompassing congenital hydrocephalus, polydactyly and renal agenesis. WDR31 is an evolutionarily conserved protein that localizes to the cilium and cilia-related compartment. Analysis from zebrafish supports the role of WDR31 in regulating the cilia morphology. The CRISPR/Cas9 knock-in (p.Arg261del) C. elegans model of the patient variant (p.Arg268*) reproduced several cilia-related defects observed in wdr-31 null mutants. Mechanistic analysis from C. elegans revealed that WDR-31 functions redundantly with ELDM-1 (ELMOD protein) and RPI-2 (RP2) to regulate the IFT trafficking through controlling the cilia entry of the BBSome. This work revealed WDR31 as a new ciliopathy protein that regulates IFT and BBSome trafficking.

scholarly journals Extracellular matrix regulates morphogenesis and function of ciliated sensory organs in Caenorhabditis elegans

2018 ◽  
Author(s):  
Deanna M. De Vore ◽  
Karla M. Knobel ◽  
Ken C.Q. Nguyen ◽  
David H. Hall ◽  
Maureen M. Barr
Keyword(s):  
Extracellular Matrix ◽  
Dendritic Morphology ◽  
C Elegans ◽  
Genes Encoding ◽  
Health And Disease ◽  
Autosomal Dominant Polycystic Kidney ◽  
Signaling Organelles ◽  
And Function

ABSTRACTCilia and extracellular vesicles (EVs) are signaling organelles that play important roles in human health and disease. In C. elegans and mammals, the Autosomal Dominant Polycystic Kidney Disease (ADPKD) gene products polycystin-1 and polycystin-2 localize to both cilia and EVs, act in the same genetic pathway, and function in a sensory capacity, suggesting ancient conservation. Hence, the nematode offers an excellent system in which to address central questions regarding the biology of cilia, EVs, and the polycystins. We discovered an unexpected role of the mec-1, mec-5, and mec-9 genes encoding extracellular matrix (ECM) components. We determined that these ECM encoding genes regulate polycystin localization and function, ciliary EV release, cilia length, dendritic morphology, and neuron-glia interactions. Abnormal ECM and fibrosis are observed in ciliopathies such as ADPKD, nephronophthisis, and Bardet-Biedl Syndrome. Our studies reveal multifaceted roles for ECM proteins in the ciliated nervous system of the worm and provide a powerful new in vivo model to study the relationship between ECM, the polycystins, and ciliopathies.

scholarly journals Evolutionarily conserved roles of Caenorhabditis elegans perilipin in lipolysis

2019 ◽  
Author(s):  
Filip Kaššák ◽  
Ahmed A Chughtai ◽  
Marta Kostrouchová
Keyword(s):  
Neutral Lipids ◽  
Physiological Role ◽  
Hormone Sensitive Lipase ◽  
Functional Connection ◽  
Regulatory Pathways ◽  
C Elegans ◽  
Evolutionarily Conserved ◽  
Eukaryotic Organisms

Neutral lipids and namely triacyl-glycerols (TAGs) are the prevalent excess energy storage molecules in all eukaryotic organisms. They are universally organized in active cytoplasmic organelles called lipid droplets (LDs) and their breakdown is performed and regulated in an evolutionarily conserved manner. In mammals, two distinct but inter-connected pathways are believed to mediate this catabolism: conventional cytoplasmic lipolysis with effector neutral lipases; and lipophagy, a specific kind of autophagy exploiting lysosomal acidic lipases. Central molecules in this regulation are LD-resident proteins, perilipins (PLINs). Our recent discovery of a sole PLIN orthologue in C. elegans offers a unique opportunity to study these regulatory pathways, provided that the interactive mechanisms are orthologous. To determine this, we employed classical genetics with genome editing tools and in vivo microscopy to provide three lines of evidence demonstrating the conserved role of the C. elegans perilipin. Firstly, we proved the common presence of a standard lipolytic apparatus on LDs. Next, we ascertained a functional connection between nematode PLIN-1 and the effector enzyme, hormone-sensitive lipase (HOSL-1). Finally, we identified lipophagy as a secondary lipolytic pathway, which is consistent with the mammalian model. Our data provide not only a proof of concept but also suggests interesting implications by questioning the physiological role of lipophagy in lipolysis.

scholarly journals Methylation of histone H3K23 blocks DNA damage in pericentric heterochromatin during meiosis

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Romeo Papazyan ◽  
Ekaterina Voronina ◽  
Jessica R Chapman ◽  
Teresa R Luperchio ◽  
Tonya M Gilbert ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Model Organism ◽  
Pericentric Heterochromatin ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
C Elegans ◽  
Evolutionarily Conserved ◽  
Established Role

Despite the well-established role of heterochromatin in protecting chromosomal integrity during meiosis and mitosis, the contribution and extent of heterochromatic histone posttranslational modifications (PTMs) remain poorly defined. Here, we gained novel functional insight about heterochromatic PTMs by analyzing histone H3 purified from the heterochromatic germline micronucleus of the model organism Tetrahymena thermophila. Mass spectrometric sequencing of micronuclear H3 identified H3K23 trimethylation (H3K23me3), a previously uncharacterized PTM. H3K23me3 became particularly enriched during meiotic leptotene and zygotene in germline chromatin of Tetrahymena and C. elegans. Loss of H3K23me3 in Tetrahymena through deletion of the methyltransferase Ezl3p caused mislocalization of meiosis-induced DNA double-strand breaks (DSBs) to heterochromatin, and a decrease in progeny viability. These results show that an evolutionarily conserved developmental pathway regulates H3K23me3 during meiosis, and our studies in Tetrahymena suggest this pathway may function to protect heterochromatin from DSBs.

scholarly journals Biological significance of a universally conserved transcription mediator in metazoan developmental signaling pathways

Development ◽  
2001 ◽  
Vol 128 (16) ◽  
pp. 3095-3104 ◽  
Author(s):  
Jae Young Kwon ◽  
Junho Lee
Keyword(s):  
Signaling Pathways ◽  
Biological Significance ◽  
Genetic Mutation ◽  
Ras Pathway ◽  
C Elegans ◽  
Physical Maps ◽  
Evolutionarily Conserved ◽  
Related Proteins

Transcription mediators are known to be required for regulated transcription in yeast and higher eukaryotes. However, little is known about the specific roles of mediators in vivo during development. In this report, we have characterized the biological functions of the C. elegans genemed-6, which is the homolog of the yeast mediator med-6. We first identified a genetic mutation in the med-6 gene by comparing genetic and physical maps and determining the molecular lesion. Next, we demonstrated that med-6 plays an important role in metazoan development by regulating the transcription of genes in evolutionarily conserved signaling pathways. We showed that med-6 is involved in the transcription of genes of the Ras pathway by showing that med-6 RNAi suppressed phenotypes associated with gain-of-function alleles oflet-23 and let-60, and enhanced those associated with a reduction-of-function allele of lin-3. We also found thatmed-6 is involved in male ray development, which is partly mediated by the Wnt pathway. As MED-6 is universally conserved, including in yeast, and the mediator-related proteins that function in vulval and male ray development are metazoan specific, our results suggest the role of med-6 as a point of convergence where signals transmitted through metazoan-specific mediator-related proteins meet. In addition, RNAi experiments inrde-1 background showed that maternal and zygotic med-6activities have distinct roles in development.

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