scholarly journals New insights into non-transcriptional regulation of mammalian core clock proteins

2020 ◽  
Vol 133 (18) ◽  
pp. jcs241174
Author(s):  
Priya Crosby ◽  
Carrie L. Partch
Keyword(s):  
Feedback Loop ◽  
Molecular Mechanisms ◽  
Negative Feedback Loop ◽  
Cellular Processes ◽  
The Core ◽  
Clock Proteins ◽  
Wide Range ◽  
Contemporary Work ◽  
Cryptochrome 1 ◽  
Activator Complex

ABSTRACTMammalian circadian rhythms drive ∼24 h periodicity in a wide range of cellular processes, temporally coordinating physiology and behaviour within an organism, and synchronising this with the external day–night cycle. The canonical model for this timekeeping consists of a delayed negative-feedback loop, containing transcriptional activator complex CLOCK–BMAL1 (BMAL1 is also known as ARNTL) and repressors period 1, 2 and 3 (PER1, PER2 and PER3) and cryptochrome 1 and 2 (CRY1 and CRY2), along with a number of accessory factors. Although the broad strokes of this system are defined, the exact molecular mechanisms by which these proteins generate a self-sustained rhythm with such periodicity and fidelity remains a topic of much research. Recent studies have identified prominent roles for a number of crucial post-transcriptional, translational and, particularly, post-translational events within the mammalian circadian oscillator, providing an increasingly complex understanding of the activities and interactions of the core clock proteins. In this Review, we highlight such contemporary work on non-transcriptional events and set it within our current understanding of cellular circadian timekeeping.

Molecular mechanisms of endolysosomal Ca2+ signalling in health and disease

2011 ◽  
Vol 439 (3) ◽  
pp. 349-378 ◽  
Author(s):  
Anthony J. Morgan ◽  
Frances M. Platt ◽  
Emyr Lloyd-Evans ◽  
Antony Galione
Keyword(s):  
Molecular Mechanisms ◽  
Cellular Processes ◽  
Late Endosomes ◽  
Wide Range ◽  
Health And Disease ◽  
Lysosome Related Organelles ◽  
Cellular Compartments ◽  
Endosomal Vesicles ◽  
Intracellular Targets

Endosomes, lysosomes and lysosome-related organelles are emerging as important Ca2+ storage cellular compartments with a central role in intracellular Ca2+ signalling. Endocytosis at the plasma membrane forms endosomal vesicles which mature to late endosomes and culminate in lysosomal biogenesis. During this process, acquisition of different ion channels and transporters progressively changes the endolysosomal luminal ionic environment (e.g. pH and Ca2+) to regulate enzyme activities, membrane fusion/fission and organellar ion fluxes, and defects in these can result in disease. In the present review we focus on the physiology of the inter-related transport mechanisms of Ca2+ and H+ across endolysosomal membranes. In particular, we discuss the role of the Ca2+-mobilizing messenger NAADP (nicotinic acid adenine dinucleotide phosphate) as a major regulator of Ca2+ release from endolysosomes, and the recent discovery of an endolysosomal channel family, the TPCs (two-pore channels), as its principal intracellular targets. Recent molecular studies of endolysosomal Ca2+ physiology and its regulation by NAADP-gated TPCs are providing exciting new insights into the mechanisms of Ca2+-signal initiation that control a wide range of cellular processes and play a role in disease. These developments underscore a new central role for the endolysosomal system in cellular Ca2+ regulation and signalling.

scholarly journals KLF2 inhibits TGF-β-mediated cancer cell motility in hepatocellular carcinoma

2020 ◽  
Vol 52 (5) ◽  
pp. 485-494 ◽  
Author(s):  
Yining Li ◽  
Shuo Tu ◽  
Yi Zeng ◽  
Cheng Zhang ◽  
Tian Deng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Motility ◽  
Cancer Cell ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Molecular Mechanisms ◽  
Luciferase Reporter ◽  
Negative Feedback Loop ◽  
Liver Malignancy ◽  
Cancer Cell Motility

Abstract Feedback regulation plays a pivotal role in determining the intensity and duration of TGF-β signaling and subsequently affecting the pathophysiological roles of TGF-β, including those in liver malignancy. KLF2, a member of the Krüppel-like factor (KLF) family transcription factors, has been implicated in impeding hepatocellular carcinoma (HCC) development. However, the underlying molecular mechanisms are not fully understood. In the present study, we found that TGF-β stimulates the expression of KLF2 gene in several HCC cell lines. KLF2 protein is able to inhibit TGF-β/Smad signaling in HCC cells as assessed by luciferase reporter assay. Further studies indicated that KLF2 inhibits the transcriptional activity of Smad2/3 and Smad4 and ameliorates TGF-β-induced target gene expression, therefore creating a novel negative feedback loop in TGF-β signaling. Functionally, stably expression of KLF2 in HCCLM3 cells attenuated TGF-β-induced cancer cell motility in wound-healing and transwell assays by interfering with TGF-β-mediated upregulation of MMP2. Together, our results revealed that KLF2 protein has a tumor-suppressive function in HCC through a negative feedback loop over TGF-β signaling.

scholarly journals Distinct Roles of HDAC3 in the Core Circadian Negative Feedback Loop Are Critical for Clock Function

Cell Reports ◽  
2016 ◽  
Vol 14 (4) ◽  
pp. 823-834 ◽  
Author(s):  
Guangsen Shi ◽  
Pancheng Xie ◽  
Zhipeng Qu ◽  
Zhihui Zhang ◽  
Zhen Dong ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Feedback Loop ◽  
Negative Feedback Loop ◽  
The Core

Mitochondrial fission and fusion

2016 ◽  
Vol 44 (6) ◽  
pp. 1725-1735 ◽  
Author(s):  
Hakjoo Lee ◽  
Yisang Yoon
Keyword(s):  
Molecular Mechanisms ◽  
Core Protein ◽  
Mitochondrial Fission ◽  
Short Review ◽  
Membrane Remodeling ◽  
Cellular Processes ◽  
The Core

Mitochondrial fission and fusion have been recognized as critical processes in the health of mitochondria and cells. Two decades of studies have generated a great deal of information about mitochondrial fission and fusion; however, still much needs to be understood for the basic molecular mechanisms of these important cellular processes. The core protein factors for mitochondrial fission and fusion are dynamin proteins that possess membrane-remodeling properties. This short review covers a recent development and understanding of the mechanisms by which these mechanochemical enzymes mediate mitochondrial fission and fusion.

scholarly journals Oxidation inhibits autophagy protein deconjugation from phagosomes to sustain MHC class II restricted antigen presentation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Laure-Anne Ligeon ◽  
Maria Pena-Francesch ◽  
Liliana Danusia Vanoaica ◽  
Nicolás Gonzalo Núñez ◽  
Deepti Talwar ◽  
...  
Keyword(s):  
Antigen Presentation ◽  
Mhc Class Ii ◽  
Antigen Processing ◽  
Redox Regulation ◽  
Molecular Mechanisms ◽  
Class Ii ◽  
Oxygen Species ◽  
Cellular Processes ◽  
Oxidative Inactivation ◽  
Wide Range

AbstractLC3-associated phagocytosis (LAP) contributes to a wide range of cellular processes and notably to immunity. The stabilization of phagosomes by the macroautophagy machinery in human macrophages can maintain antigen presentation on MHC class II molecules. However, the molecular mechanisms involved in the formation and maturation of the resulting LAPosomes are not completely understood. Here, we show that reactive oxygen species (ROS) produced by NADPH oxidase 2 (NOX2) stabilize LAPosomes by inhibiting LC3 deconjugation from the LAPosome cytosolic surface. NOX2 residing in the LAPosome membrane generates ROS to cause oxidative inactivation of the protease ATG4B, which otherwise releases LC3B from LAPosomes. An oxidation-insensitive ATG4B mutant compromises LAP and thereby impedes sustained MHC class II presentation of exogenous Candida albicans antigens. Redox regulation of ATG4B is thereby an important mechanism for maintaining LC3 decoration of LAPosomes to support antigen processing for MHC class II presentation.

scholarly journals Central and peripheral circadian oscillator mechanisms in flies and mammals

2002 ◽  
Vol 115 (17) ◽  
pp. 3369-3377 ◽  
Author(s):  
Nicholas R. J. Glossop ◽  
Paul E. Hardin
Keyword(s):  
Feedback Loop ◽  
Molecular Mechanisms ◽  
Circadian Oscillator ◽  
The Core ◽  
Peripheral Oscillators ◽  
Circadian Oscillators ◽  
Core Components ◽  
Central Oscillator ◽  
Molecular Components

Circadian oscillators are cell-autonomous time-keeping mechanisms that reside in diverse tissues in many organisms. In flies and mice, the core molecular components that sustain these oscillators are highly conserved, but the functions of some of these components appear to have diverged significantly. One possible reason for these differences is that previous comparisons have focused primarily on the central oscillator of the mouse and peripheral oscillators in flies. Recent research on mouse and Drosophila peripheral oscillators shows that the function of the core components between these organisms may be more highly conserved than was first believed, indicating the following: (1) that central and peripheral oscillators in flies do not necessarily have the same molecular mechanisms;(2) that mammalian central oscillators are regulated differently from peripheral oscillators; and (3) that different peripheral oscillators within and across species show striking similarities. The core feedback loop in peripheral oscillators might therefore be functionally well conserved, and central oscillators could be specialized versions of a basic oscillator design.

scholarly journals Expression of the gene for Dec2, a basic helix–loop–helix transcription factor, is regulated by a molecular clock system

2004 ◽  
Vol 382 (1) ◽  
pp. 43-50 ◽  
Author(s):  
Hidenori HAMAGUCHI ◽  
Katsumi FUJIMOTO ◽  
Takeshi KAWAMOTO ◽  
Mitsuhide NOSHIRO ◽  
Koji MAEMURA ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Feedback Loop ◽  
Molecular Mechanisms ◽  
Regulatory Protein ◽  
Circadian Oscillation ◽  
Negative Feedback Loop ◽  
Mrna Levels ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
E Boxes

Dec2, a member of the basic helix–loop–helix superfamily, is a recently confirmed regulatory protein for the clockwork system. Transcripts of Dec2, as well as those of its related gene Dec1, exhibit a striking circadian oscillation in the suprachiasmatic nucleus, and Dec2 inhibits transcription from the Per1 promoter induced by Clock/Bmal1 [Honma, Kawamoto, Takagi, Fujimoto, Sato, Noshiro, Kato and Honma (2002) Nature (London) 419, 841–844]. It is known that mammalian circadian rhythms are controlled by molecular clockwork systems based on negative-feedback loop(s), but the molecular mechanisms for the circadian regulation of Dec2 gene expression have not been clarified. We show here that transcription of the Dec2 gene is regulated by several clock molecules and a negative-feedback loop. Luciferase and gel retardation assays showed that expression of Dec2 was negatively regulated by binding of Dec2 or Dec1 to two CACGTG E-boxes in the Dec2 promoter. Forced expression of Clock/Bmal1 and Clock/Bmal2 markedly increased Dec2 mRNA levels, and up-regulated the transcription of the Dec2 gene through the CACGTG E-boxes. Like Dec, Cry and Per also suppressed Clock/Bmal-induced transcription from the Dec2 promoter. Moreover, the circadian expression of Dec2 transcripts was abolished in the kidney of Clock/Clock mutant mice. These findings suggest that the Clock/Bmal heterodimer enhances Dec2 transcription via the CACGTG E-boxes, whereas the induced transcription is suppressed by Dec2, which therefore must contribute to its own rhythmic expression. In addition, Cry and Per may also modulate Dec2 transcription.

scholarly journals Mechanochemical feedback and control of endocytosis and membrane tension

2017 ◽  
Author(s):  
Joseph Jose Thottacherry ◽  
Anita Joanna Kosmalska ◽  
Alberto Elosegui-Artola ◽  
Susav Pradhan ◽  
Sumit Sharma ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Membrane Trafficking ◽  
Feedback Loop ◽  
Negative Feedback Loop ◽  
Dependent Manner ◽  
Homeostatic Regulation ◽  
Membrane Tension ◽  
Cellular Processes ◽  
Tightly Coupled ◽  
And Control

AbstractPlasma membrane tension is an important factor that regulates many key cellular processes. Membrane trafficking is tightly coupled to membrane tension and can modulate the latter by addition or removal of the membrane. However, the cellular pathway(s) involved in these processes are poorly understood. Here we find that, among a number of endocytic processes operating simultaneously at the cell surface, a dynamin and clathrin-independent pathway, the CLIC/GEEC (CG) pathway, is rapidly and specifically upregulated upon reduction of tension. On the other hand, inhibition of the CG pathway results in lower membrane tension, while up regulation significantly enhances membrane tension. We find that vinculin, a well-studied mechanotransducer, mediates the tension-dependent regulation of the CG pathway. Vinculin negatively regulates a key CG pathway regulator, GBF1, at the plasma membrane in a tension dependent manner. Thus, the CG pathway operates in a negative feedback loop with membrane tension which leads to a homeostatic regulation of membrane tension.

scholarly journals Molecular and Cellular Mechanisms Affected in ALS

2020 ◽  
Vol 10 (3) ◽  
pp. 101 ◽  
Author(s):  
Laura Le Gall ◽  
Ekene Anakor ◽  
Owen Connolly ◽  
Udaya Vijayakumar ◽  
William Duddy ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Late Onset ◽  
Glutamate Excitotoxicity ◽  
Cellular Mechanisms ◽  
Cellular Processes ◽  
Onset Condition ◽  
Wide Range ◽  
Sporadic Cases ◽  
Aberrant Rna

Amyotrophic lateral sclerosis (ALS) is a terminal late-onset condition characterized by the loss of upper and lower motor neurons. Mutations in more than 30 genes are associated to the disease, but these explain only ~20% of cases. The molecular functions of these genes implicate a wide range of cellular processes in ALS pathology, a cohesive understanding of which may provide clues to common molecular mechanisms across both familial (inherited) and sporadic cases and could be key to the development of effective therapeutic approaches. Here, the different pathways that have been investigated in ALS are summarized, discussing in detail: mitochondrial dysfunction, oxidative stress, axonal transport dysregulation, glutamate excitotoxicity, endosomal and vesicular transport impairment, impaired protein homeostasis, and aberrant RNA metabolism. This review considers the mechanistic roles of ALS-associated genes in pathology, viewed through the prism of shared molecular pathways.

scholarly journals Formation of a repressive complex in the mammalian circadian clock is mediated by the secondary pocket of CRY1

2017 ◽  
Vol 114 (7) ◽  
pp. 1560-1565 ◽  
Author(s):  
Alicia K. Michael ◽  
Jennifer L. Fribourgh ◽  
Yogarany Chelliah ◽  
Colby R. Sandate ◽  
Greg L. Hura ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Single Point ◽  
Point Mutations ◽  
Binding Pocket ◽  
Pas Domain ◽  
Precise Control ◽  
The Core ◽  
Helix Loop Helix ◽  
Clock Proteins ◽  
Cryptochrome 1

The basic helix–loop–helix PAS domain (bHLH-PAS) transcription factor CLOCK:BMAL1 (brain and muscle Arnt-like protein 1) sits at the core of the mammalian circadian transcription/translation feedback loop. Precise control of CLOCK:BMAL1 activity by coactivators and repressors establishes the ∼24-h periodicity of gene expression. Formation of a repressive complex, defined by the core clock proteins cryptochrome 1 (CRY1):CLOCK:BMAL1, plays an important role controlling the switch from repression to activation each day. Here we show that CRY1 binds directly to the PAS domain core of CLOCK:BMAL1, driven primarily by interaction with the CLOCK PAS-B domain. Integrative modeling and solution X-ray scattering studies unambiguously position a key loop of the CLOCK PAS-B domain in the secondary pocket of CRY1, analogous to the antenna chromophore-binding pocket of photolyase. CRY1 docks onto the transcription factor alongside the PAS domains, extending above the DNA-binding bHLH domain. Single point mutations at the interface on either CRY1 or CLOCK disrupt formation of the ternary complex, highlighting the importance of this interface for direct regulation of CLOCK:BMAL1 activity by CRY1.

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