scholarly journals Phosphorylation and Ubiquitylation Regulate Protein Trafficking, Signaling, and the Biogenesis of Primary Cilia

2021 ◽  
Vol 9 ◽  
Author(s):  
Elena A. May ◽  
Tommy J. Sroka ◽  
David U. Mick
Keyword(s):  
Protein Trafficking ◽  
Primary Cilia ◽  
Molecular Mechanisms ◽  
Post Translational Modifications ◽  
Quiescent Cells ◽  
Cellular Environment ◽  
Regulate Protein ◽  
Cycle Dependent ◽  
External Signals ◽  
Signaling Components

The primary cilium is a solitary, microtubule-based membrane protrusion extending from the surface of quiescent cells that senses the cellular environment and triggers specific cellular responses. The functions of primary cilia require not only numerous different components but also their regulated interplay. The cilium performs highly dynamic processes, such as cell cycle-dependent assembly and disassembly as well as delivery, modification, and removal of signaling components to perceive and process external signals. On a molecular level, these processes often rely on a stringent control of key modulatory proteins, of which the activity, localization, and stability are regulated by post-translational modifications (PTMs). While an increasing number of PTMs on ciliary components are being revealed, our knowledge on the identity of the modifying enzymes and their modulation is still limited. Here, we highlight recent findings on cilia-specific phosphorylation and ubiquitylation events. Shedding new light onto the molecular mechanisms that regulate the sensitive equilibrium required to maintain and remodel primary cilia functions, we discuss their implications for cilia biogenesis, protein trafficking, and cilia signaling processes.

scholarly journals Post-translational Modifications are Required for Circadian Clock Regulation in Vertebrates

2019 ◽  
Vol 20 (5) ◽  
pp. 332-339 ◽  
Author(s):  
Yoshimi Okamoto-Uchida ◽  
Junko Izawa ◽  
Akari Nishimura ◽  
Atsuhiko Hattori ◽  
Nobuo Suzuki ◽  
...  
Keyword(s):  
Transcriptional Activity ◽  
Molecular Mechanisms ◽  
Feedback Loops ◽  
Circadian Clocks ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Negative Feedback Loops ◽  
Genetic Techniques ◽  
External Signals ◽  
Exact Timing

Circadian clocks are intrinsic, time-tracking systems that bestow upon organisms a survival advantage. Under natural conditions, organisms are trained to follow a 24-h cycle under environmental time cues such as light to maximize their physiological efficiency. The exact timing of this rhythm is established via cell-autonomous oscillators called cellular clocks, which are controlled by transcription/ translation-based negative feedback loops. Studies using cell-based systems and genetic techniques have identified the molecular mechanisms that establish and maintain cellular clocks. One such mechanism, known as post-translational modification, regulates several aspects of these cellular clock components, including their stability, subcellular localization, transcriptional activity, and interaction with other proteins and signaling pathways. In addition, these mechanisms contribute to the integration of external signals into the cellular clock machinery. Here, we describe the post-translational modifications of cellular clock regulators that regulate circadian clocks in vertebrates.

scholarly journals Post-translational modifications of EZH2 in cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Zhongwei Li ◽  
Minle Li ◽  
Diandian Wang ◽  
Pingfu Hou ◽  
Xintian Chen ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Target Gene ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Therapeutic Potential ◽  
Post Translational Modifications ◽  
Polycomb Repressive Complex 2 ◽  
Binding Partners ◽  
Regulate Protein ◽  
Main Component

AbstractEnhancer of zeste homolog 2 (EZH2), as a main component of Polycomb Repressive Complex 2, catalyzes histone H3K27me3 to silence its target gene expression. EZH2 upregulation results in cancer development and poor prognosis of cancer patients. Post-translational modifications (PTMs) are important biological events in cancer progression. PTMs regulate protein conformation and diversity functions. Recently, mounting studies have demonstrated that EZH2 stability, histone methyltransferase activity, localization, and binding partners can be regulated by PTMs, including phosphorylation, O-GlcNAcylation, acetylation, methylation and ubiquitination. However, the detailed molecular mechanisms of the EZH2-PTMs and whether other types of PTMs occur in EZH2 remain largely unclear. This review presents an overview of different roles of EZH2 modification and EZH2-PTMs crosstalk during tumorigenesis and cancer metastasis. We also discussed the therapeutic potential of targeting EZH2 modifications for cancer therapy.

scholarly journals Ift172 conditional knockout mice exhibit rapid retinal degeneration and protein trafficking defects

2017 ◽  
Author(s):  
Priya R Gupta ◽  
Nachiket Pendse ◽  
Scott H Greenwald ◽  
Mihoko Leon ◽  
Qin Liu ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Protein Trafficking ◽  
Primary Cilia ◽  
Molecular Mechanisms ◽  
Outer Nuclear Layer ◽  
Intraflagellar Transport ◽  
Conditional Knockout ◽  
Photoreceptor Outer Segments ◽  
Outer Segments ◽  
Trafficking Defects

AbstractIntraflagellar transport (IFT) is a bidirectional transport process that occurs along primary cilia and specialized sensory cilia, such as photoreceptor outer-segments. Genes coding for various IFT components are associated with ciliopathies. Mutations in IFT172 lead to diseases ranging from isolated retinal degeneration to severe syndromic ciliopathies. In this study, we created a mouse model of IFT172-associated retinal degeneration to investigate the ocular disease mechanism. We found that depletion of IFT172 in rod photoreceptors leads to a rapid degeneration of the retina, with severely reduced electroretinography responses by one month and complete outer-nuclear layer degeneration by two months. We investigated molecular mechanisms of degeneration and show that IFT172 protein reduction leads to mislocalization of specific photoreceptor outer-segments proteins (RHO, RP1, IFT139), aberrant light-driven translocation of alpha transducin and altered localization of glioma-associated oncogene family member 1 (GLI1). This murine model recapitulates the retinal phenotype seen in patients with IFT172-associated blindness and can be used for in vivo testing of ciliopathy therapies.

scholarly journals Conserved Molecular Mechanisms Underlying Homeostasis of the Golgi Complex

2010 ◽  
Vol 2010 ◽  
pp. 1-9 ◽  
Author(s):  
Cathal Wilson ◽  
Antonella Ragnini-Wilson
Keyword(s):  
Golgi Complex ◽  
Protein Trafficking ◽  
Secretory Pathway ◽  
Molecular Mechanisms ◽  
Underlying Mechanism ◽  
Central Function ◽  
Sequential Processing ◽  
The Face ◽  
Regulate Protein ◽  
Dynamic Structures

The Golgi complex performs a central function in the secretory pathway in the sorting and sequential processing of a large number of proteins destined for other endomembrane organelles, the plasma membrane, or secretion from the cell, in addition to lipid metabolism and signaling. The Golgi apparatus can be regarded as a self-organizing system that maintains a relatively stable morphofunctional organization in the face of an enormous flux of lipids and proteins. A large number of the molecular players that operate in these processes have been identified, their functions and interactions defined, but there is still debate about many aspects that regulate protein trafficking and, in particular, the maintenance of these highly dynamic structures and processes. Here, we consider how an evolutionarily conserved underlying mechanism based on retrograde trafficking that uses lipids, COPI, SNAREs, and tethers could maintain such a homeodynamic system.

Molecular basis of ciliary defects caused by compound heterozygous IFT144/WDR19 mutations found in cranioectodermal dysplasia

2021 ◽  
Author(s):  
Yamato Ishida ◽  
Takuya Kobayashi ◽  
Shuhei Chiba ◽  
Yohei Katoh ◽  
Kazuhisa Nakayama
Keyword(s):  
Protein Trafficking ◽  
Primary Cilia ◽  
Intraflagellar Transport ◽  
Missense Variant ◽  
Cellular Level ◽  
Compound Heterozygous ◽  
Hypomorphic Allele ◽  
Genes Encoding ◽  
Specific Proteins ◽  
Compound Heterozygous Mutations

Abstract Primary cilia contain specific proteins to achieve their functions as cellular antennae. Ciliary protein trafficking is mediated by the intraflagellar transport (IFT) machinery containing the IFT-A and IFT-B complexes. Mutations in genes encoding the IFT-A subunits (IFT43, IFT121/WDR35, IFT122, IFT139/TTC21B, IFT140, and IFT144/WDR19) often result in skeletal ciliopathies, including cranioectodermal dysplasia (CED). We here characterized the molecular and cellular defects of CED caused by compound heterozygous mutations in IFT144 [the missense variant IFT144(L710S) and the nonsense variant IFT144(R1103*)]. These two variants were distinct with regard to their interactions with other IFT-A subunits and with the IFT-B complex. When exogenously expressed in IFT144-knockout (KO) cells, IFT144(L710S) as well as IFT144(WT) rescued both moderately compromised ciliogenesis and the abnormal localization of ciliary proteins. As the homozygous IFT144(L710S) mutation was found to cause autosomal recessive retinitis pigmentosa, IFT144(L710S) is likely to be hypomorphic at the cellular level. In striking contrast, the exogenous expression of IFT144(R1103*) in IFT144-KO cells exacerbated the ciliogenesis defects. The expression of IFT144(R1103*) together with IFT144(WT) restored the abnormal phenotypes of IFT144-KO cells. However, the coexpression of IFT144(R1103*) with the hypomorphic IFT144(L710S) variant in IFT144-KO cells, which mimics the genotype of compound heterozygous CED patients, resulted in severe ciliogenesis defects. Taken together, these observations demonstrate that compound heterozygous mutations in IFT144 cause severe ciliary defects via a complicated mechanism, where one allele can cause severe ciliary defects when combined with a hypomorphic allele.

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.

Modelling molecular mechanisms within their cellular environment

1999 ◽  
Vol 71 (1-3) ◽  
pp. 263-265
Author(s):  
Vassily Hatzimanikatis ◽  
James E. Bailey
Keyword(s):  
Molecular Mechanisms ◽  
Cellular Environment

scholarly journals Transmembrane-truncated αvβ3 integrin retains high affinity for ligand binding: evidence for an ‘inside-out’ suppressor?

1998 ◽  
Vol 330 (2) ◽  
pp. 861-869 ◽  
Author(s):  
J. Raj MEHTA ◽  
Beate DIEFENBACH ◽  
Alex BROWN ◽  
Eilish CULLEN ◽  
Alfred JONCZYK ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Wound Repair ◽  
Molecular Mechanisms ◽  
Full Length ◽  
Αvβ3 Integrin ◽  
Cytoplasmic Domains ◽  
Bivalent Cation ◽  
High Affinity ◽  
Cellular Environment

The molecular mechanisms of αvβ3 integrin affinity regulation have important biological implications in tumour development, wound repair and angiogenesis. We expressed, purified and characterized recombinant forms of human αvβ3 (r-αvβ3) and compared the activation state of these with αvβ3 in its cellular environment. The ligand specificity and selectivity of recombinant full-length and double transmembrane truncations of r-αvβ3 cloned in BacPAK6 vectors and expressed in Sf9 and High Five insect cells were compared with those of native placental αvβ3 and the receptor in situ on the cell surface. r-αvβ3 integrins were purified by affinity chromatography from detergent extracts of cells (full-length), and from the culture medium of cells expressing double-truncated r-αvβ3. r-αvβ3 had the same epitopes, ligand-binding specificities, bivalent cation requirements and susceptibility to RGD-containing peptides as native αvβ3. On M21-L4 melanoma cells, αvβ3 mediated binding to vitronectin, but not to fibrinogen unless activated with Mn2+. Non-activated αIIbβ3 integrin as control in M21-L-IIb cells had the opposite profile, mediating binding to fibrinogen, but not to vitronectin unless activated with Mn2+. Thus these receptors had moderate to low ligand affinity. In marked contrast, purified αvβ3 receptors, with or without transmembrane and cytoplasmic domains, were constitutively of high affinity and able to bind strongly to vitronectin, fibronectin and fibrinogen under physiological conditions. Our data suggest that, in contrast with the positive regulation of αIIbβ3 in situ, intracellular controls lower the affinity of αvβ3, and the cytoplasmic domains may act as a target for negative regulators of αvβ3 activity.

scholarly journals CNPY4 inhibits the Hedgehog pathway by modulating membrane sterol lipids

2021 ◽  
Author(s):  
Megan Lo ◽  
Amnon Sharir ◽  
Michael D Paul ◽  
Hayarpi Torosyan ◽  
Christopher Agnew ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Primary Cilia ◽  
Molecular Mechanisms ◽  
Negative Regulator ◽  
Membrane Composition ◽  
Hh Signaling ◽  
Pathway Regulation ◽  
Patched 1 ◽  
Cancer Signal Transduction

The Hedgehog (HH) pathway is critical for development and adult tissue homeostasis. Aberrant HH signaling can cause congenital malformations, such as digit anomalies and holoprosencephaly, and other diseases, including cancer. Signal transduction is initiated by HH ligand binding to the Patched 1 (PTCH1) receptor on primary cilia, thereby releasing inhibition of Smoothened (SMO), a HH pathway activator. Although cholesterol and several oxysterol lipids, which are enriched in the ciliary membrane, play a crucial role in HH activation, the molecular mechanisms governing the regulation of these lipid molecules remain unresolved. Here, we identify Canopy 4 (CNPY4), a Saposin-like protein, as a regulator of the HH pathway that controls membrane sterol lipid levels. Cnpy4—/— embryos exhibit multiple defects consistent with HH signaling perturbations, most notably changes in digit number. Knockdown of Cnpy4 hyperactivates the HH pathway at the level of SMO in vitro, and elevates membrane levels of accessible sterol lipids such as cholesterol, an endogenous ligand involved in SMO activation. Thus, our data demonstrate that CNPY4 is a negative regulator that fine-tunes the initial steps of HH signal transduction, revealing a previously undescribed facet of HH pathway regulation that operates through control of membrane composition.

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