Mahogunin Ring Finger-1 (MGRN1), a Multifaceted Ubiquitin Ligase: Recent Unraveling of Neurobiological Mechanisms

Upadhyay, Arun; Amanullah, Ayeman; Chhangani, Deepak; Mishra, Ribhav; Prasad, Amit; Mishra, Amit Kumar

doi:10.1007/s12035-015-9379-8

Cited by 24 publications

(28 citation statements)

References 113 publications

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“…The process of ubiquitylation, whereby a ubiquitin moiety is covalently fused to a protein through an electron-rich group (such as internal lysine, cysteine, serine or threonine residues, or the N-terminal amino group (69)), can target the protein for localization to a different part of the cell or for degradation using various combinations of mono- or polyubiquitylation (70). The E3 ligase, Mahogunin ring-finger 1 (Mgrn1), polyubiquitylates α-tubulin to target it for degradation (71,72). Mgrn1-null mouse mutants exhibit phenotypes such as late-onset spongiform neurodegeneration and laterality defects such as congenital heart defects and situs inversus (48,73).…”

Section: Resultsmentioning

confidence: 99%

Conserved roles for cytoskeletal components in determining laterality

McDowell

Lemire

Paré

et al. 2016

Integrative Biology

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SUMMARY Consistently-biased left-right (LR) patterning is required for the proper placement of organs including the heart and viscera. The LR axis is especially fascinating as an example of multi-scale pattern formation, since here chiral events at the subcellular level are integrated and amplified into asymmetric transcriptional cascades and ultimately into the anatomical patterning of the entire body. In contrast to the other two body axes, there is considerable controversy about the earliest mechanisms of embryonic laterality. Many molecular components of asymmetry have not been widely tested among phyla with diverse bodyplans, and it is unknown whether parallel (redundant) pathways may exist that could reverse abnormal asymmetry states at specific checkpoints in development. To address conservation of the early steps of LR patterning, we used the Xenopus laevis (frog) embryo to functionally test a number of protein targets known to direct asymmetry in plants, fruit fly, and rodent. Using the same reagents that randomize asymmetry in Arabidopsis, Drosophila, and mouse embryos, we show that manipulation of the microtubule and actin cytoskeleton immediately post-fertilization, but not later, results in laterality defects in Xenopus embryos. Moreover, we observed organ-specific randomization effects and a striking dissociation of organ situs from effects on the expression of left side control genes, which parallel data from Drosophila and mouse. Remarkably, some early manipulations that disrupt laterality of transcriptional asymmetry determinants can be subsequently “rescued” by the embryo, resulting in normal organ situs. These data reveal the existence of novel corrective mechanisms, demonstrate that asymmetric expression of Nodal is not a definitive marker of laterality, and suggest the existence of amplification pathways that connect early cytoskeletal processes to control of organ situs bypassing Nodal. Counter to alternative models of symmetry breaking during neurulation (via ciliary structures absent in many phyla), our data suggest a widely-conserved role for the cytoskeleton in regulating left-right axis formation immediately after fertilization of the egg. The novel mechanisms that rescue organ situs, even after incorrect expression of genes previously considered to be left-side master regulators, suggest LR patterning as a new context in which to explore multi-scale redundancy and integration of patterning from the subcellular structure to the entire bodyplan.

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Section: Resultsmentioning

confidence: 99%

Conserved roles for cytoskeletal components in determining laterality

McDowell

Lemire

Paré

et al. 2016

Integrative Biology

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“…Because the Gdu1D phenotype evidently requires LOG2, a simple model in which LOG2 ubiquitinates and down-regulates GDU1 abundance and function was deemed untenable. LOG2 is homologous to MAHOGUNIN RING FINGER 1 (MGRN1), a gene that antagonizes melanocortin signaling and regulates neurogenesis in mammals (17). Whereas GDU orthologs are unknown in mammals, rat MGRN1 ubiquitinated the cytosolic region of GDU1 in vitro and partially complemented a log2 loss-of-function mutation in vivo (18), demonstrating an analogous function between these ubiquitin ligases.…”

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confidence: 99%

Control of Amino Acid Homeostasis by a Ubiquitin Ligase-Coactivator Protein Complex

Guerra

Chapiro

Pratelli

et al. 2017

Journal of Biological Chemistry

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Edited by James N. SiedowIntercellular amino acid transport is essential for the growth of all multicellular organisms, and its dysregulation is implicated in developmental disorders. By an unknown mechanism, amino acid efflux is stimulated in plants by overexpression of a membrane-localized protein (GLUTAMINE DUMPER 1 (GDU1)) that requires a ubiquitin ligase (LOSS OF GDU 2 (LOG2). Here we further explore the physiological consequences of the interaction between these two proteins. LOG2 ubiquitin ligase activity is necessary for GDU1-dependent tolerance to exogenous amino acids, and LOG2 self-ubiquitination was markedly stimulated by the GDU1 cytosolic domain, suggesting that GDU1 functions as an adaptor or coactivator of amino acid exporter(s). However, other consequences more typical of a ligase-substrate relationship are observed: disruption of the LOG2 gene increased the in vivo half-life of GDU1, mass spectrometry confirmed that LOG2 ubiquitinates GDU1 at cytosolic lysines, and GDU1 protein levels decreased upon coexpression with active, but not enzymatically inactive LOG2. Altogether these data indicate LOG2 negatively regulates GDU1 protein accumulation by a mechanism dependent upon cytosolic GDU1 lysines. Although GDU1-lysine substituted protein exhibited diminished in vivo ubiquitination, overexpression of GDU1 lysine mutants still conferred amino acid tolerance in a LOG2-dependent manner, consistent with GDU1 being both a substrate and facilitator of LOG2 function. From these data, we offer a model in which GDU1 activates LOG2 to stimulate amino acid export, a process that could be negatively regulated by GDU1 ubiquitination and LOG2 self-ubiquitination.

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“…Apart from classical proteasomal degradation system, another pathway called chaperone‐assisted proteasomal degradation is also present inside the cells. This pathway is also an example of integration of cellular chaperone machinery with the proteasomal machinery to degrade the substrate proteins . Similar to the indispensable roles played by chaperones in lysosomal degradatory pathways, they also have a fair bit of responsibilities in proteasomal pathway of degradation.…”

Section: Evolved Sustenance Of Cells Under Stress Conditions: Multiplmentioning

confidence: 99%

Proteasome‐mediated proteostasis: Novel medicinal and pharmacological strategies for diseases

Mishra

Upadhyay

Prajapati

et al. 2018

Medicinal Research Reviews

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Proteins actively participate in a wide range of cellular physiological functions. But aggregation of proteins results in cytotoxicity, and unwanted aggregation of misfolded proteins often causes many diseases. During abnormal protein aggregation events, cells try to cope against such deleterious consequences because of the remarkable functional attempts of two distinct proteolytic mechanisms. These tightly regulative and signaling mechanisms are autophagy pathway and ubiquitin proteasome system. Proteasome complex system holds the elimination capacity of intracellular aberrant protein aggregation. Despite the considerable progress that has been achieved, which elucidates wide function and diverse roles of proteasome system, still several crucial problems remain unanswered. For example, how the complex proteasomes assembly and their interactive pathways determine the precise sense of several proteotoxic insults, which can severely affect the cell survival and homeostasis? The specific degradation of various aberrant proteins that can disturb cellular homeostasis is achieved by proper proteasome functionality, which is yet another unclear and critical challenge. Therefore, a better understanding of the various cellular signaling mechanisms composing the proteasome machinery carries broad therapeutic implications linked with proteopathies. This article signifies the urgent need, which is now crucial for us to improve our understanding of the proteasome architecture, structure, and functions that span multiple level strategies from the molecular level to the cellular level. This systematic in-depth information of proteasome may be helpful in the near future to design a new molecular framework based on intrinsic and extrinsic cellular mechanisms that drive the assembly of proteasome to induce cellular survival against proteostasis imbalance and disease conditions.

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Mahogunin Ring Finger-1 (MGRN1), a Multifaceted Ubiquitin Ligase: Recent Unraveling of Neurobiological Mechanisms

Cited by 24 publications

References 113 publications

Conserved roles for cytoskeletal components in determining laterality

Conserved roles for cytoskeletal components in determining laterality

Control of Amino Acid Homeostasis by a Ubiquitin Ligase-Coactivator Protein Complex

Proteasome‐mediated proteostasis: Novel medicinal and pharmacological strategies for diseases

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