scholarly journals E3 ubiquitin ligase-mediated regulation of vertebrate ocular development; new insights into the function of SIAH enzymes

2021 ◽  
Vol 49 (1) ◽  
pp. 327-340
Author(s):  
Warlen Pereira Piedade ◽  
Jakub K. Famulski
Keyword(s):  
Protein Function ◽  
Cell Function ◽  
Developmental Stages ◽  
E3 Ligase ◽  
Critical Time ◽  
26S Proteasome ◽  
Model Organisms ◽  
Ocular Development ◽  
Seven In Absentia

Developmental regulation of the vertebrate visual system has been a focus of investigation for generations as understanding this critical time period has direct implications on our understanding of congenital blinding disease. The majority of studies to date have focused on transcriptional regulation mediated by morphogen gradients and signaling pathways. However, recent studies of post translational regulation during ocular development have shed light on the role of the ubiquitin proteasome system (UPS). This rather ubiquitous yet highly diverse system is well known for regulating protein function and localization as well as stability via targeting for degradation by the 26S proteasome. Work from many model organisms has recently identified UPS activity during various milestones of ocular development including retinal morphogenesis, retinal ganglion cell function as well as photoreceptor homeostasis. In particular work from flies and zebrafish has highlighted the role of the E3 ligase enzyme family, Seven in Absentia Homologue (Siah) during these events. In this review, we summarize the current understanding of UPS activity during Drosophila and vertebrate ocular development, with a major focus on recent findings correlating Siah E3 ligase activity with two major developmental stages of vertebrate ocular development, retinal morphogenesis and photoreceptor specification and survival.

scholarly journals Multi-omic analysis reveals the biochemical changes underpinning the varied phenotypes of the Arabidopsis long-period mutant rve 4 6 8

2021 ◽  
Author(s):  
Sabine Scandola ◽  
Devang Mehta ◽  
Maria C Rodriguez ◽  
Qiaomu Li ◽  
Richard Glen Uhrig
Keyword(s):  
Plant Cell ◽  
Protein Function ◽  
Cell Function ◽  
26S Proteasome ◽  
Circadian Oscillation ◽  
Wild Type ◽  
Leaf Surface Area ◽  
Proteasome Subunits ◽  
Cell Processes ◽  
Delayed Flowering

Plants are able to sense changes in their light environments, such as the onset of day and night, as well as anticipate these changes in order to adapt and survive. Central to this ability is the plant circadian clock, a molecular circuit that precisely orchestrates plant cell processes over the course of a day. REVEILLE proteins (RVEs) are recently discovered members of the plant circadian circuitry that activate the evening complex and PRR genes to maintain regular circadian oscillation. The RVE 8 protein and its two homologs, RVE 4 and 6, have been shown to limit the length of the circadian period, with rve 4 6 8 triple-knockout plants possessing an elongated period along with increased leaf surface area, biomass and delayed flowering relative to wild-type Col-0 plants. Here, using a multi-omics approach consisting of phenomics, transcriptomics, proteomics, and metabolomics we demonstrate how RVE8-like proteins impact diel plant cell function and draw novel connections to a number of plant cell processes that underpin the growth and development phenotypes observed in rve 4 6 8 plants. In particular, we reveal that loss of RVE8-like proteins results in altered carbohydrate, organic acid and lipid metabolism, including a starch excess phenotype at ZT0. We further demonstrate that RVE8-like proteins have a unique impact on the abundance and phosphorylation of 26S proteasome subunits, in addition to impacting the abundance and phosphorylation status of a number of protein kinases. Overall, this robust, multi-omic dataset, provides substantial new insights into RVE8-like protein function and the far reaching impact RVE8-like proteins have on the diel plant cell environment.

scholarly journals Systematic identification of A-to-I RNA editing in zebrafish development and adult organs

2021 ◽  
Author(s):  
Ilana Buchumenski ◽  
Karoline Holler ◽  
Lior Appelbaum ◽  
Eli Eisenberg ◽  
Jan Philipp Junker ◽  
...  
Keyword(s):  
Rna Editing ◽  
Developmental Stages ◽  
Model Organisms ◽  
Protein Diversity ◽  
Zebrafish Development ◽  
Physiological Conditions ◽  
Editing Activity ◽  
Maternal Mrnas ◽  
Systematic Identification

Abstract A-to-I RNA editing is a common post transcriptional mechanism, mediated by the Adenosine deaminase that acts on RNA (ADAR) enzymes, that increases transcript and protein diversity. The study of RNA editing is limited by the absence of editing maps for most model organisms, hindering the understanding of its impact on various physiological conditions. Here, we mapped the vertebrate developmental landscape of A-to-I RNA editing, and generated the first comprehensive atlas of editing sites in zebrafish. Tens of thousands unique editing events and 149 coding sites were identified with high-accuracy. Some of these edited sites are conserved between zebrafish and humans. Sequence analysis of RNA over seven developmental stages revealed high levels of editing activity in early stages of embryogenesis, when embryos rely on maternal mRNAs and proteins. In contrast to the other organisms studied so far, the highest levels of editing were detected in the zebrafish ovary and testes. This resource can serve as the basis for understanding of the role of editing during zebrafish development and maturity.

scholarly journals Neurofibromin is essential to maintain metabolic function and sustain life in the adult mouse

2018 ◽  
Author(s):  
Ashley N Turner ◽  
Maria S Johnson ◽  
Stephanie N Brosius ◽  
Brennan S. Yoder ◽  
Kevin Yang ◽  
...  
Keyword(s):  
Protein Function ◽  
Adult Mouse ◽  
Developmental Stages ◽  
Mouse Genetics ◽  
Ras Signaling ◽  
Metabolic Dysfunction ◽  
Lethal Phenotype ◽  
Pathogenic Variants ◽  
Domain Protein

AbstractThe consequences of pathogenic variants in the NF1 gene can manifest in numerous tissues as a result of loss of neurofibromin protein function(s). A known function of NF1 is negative regulation of p21ras signaling via a GTPase activating (Ras-GAP) domain. Besides modulation of Ras signaling as a tumor suppressor, other functions of this multi-domain protein are less clear. Biallelic inactivation of NF1 leads to an embryonic lethal phenotype, while neurofibromin is expressed at varying levels in most tissues beyond developmental stages. Taking advantage of the mouse genetics toolkit, we established novel tamoxifen-inducible systemic knockout Nf1 mouse models (C57BL/6) to gain a better understanding of the role of Nf1 in the adult (3-4 months) mouse. Following inactivation of floxed Nf1 alleles, adult CAGGCre-ERTM;Nf14F/4F mice lose function of Nf1 systemically. Both male and female animals do not survive beyond 11 days post-tamoxifen induction and exhibit histological changes in multiple tissues. During this acute crisis, CAGGCre-ERTM;Nf14F/4F mice are not able to maintain body temperature or body mass, and expend all adipose tissue; however, they continue to consume food and absorb calories comparable to littermate-paired controls. Targeted metabolite analyses and indirect calorimetry studies revealed altered fat metabolism, amino acid metabolism and energy expenditure, with animals undergoing metabolic crisis and torpor-like states. Thermoneutral conditions accelerated the acute, lethal phenotype coincident with lower food intake. This study reveals that systemic loss of neurofibromin in the adult mouse induces metabolic dysfunction and lethality, thus highlighting potential functions of this multi-domain protein in addition to tumor suppression.

scholarly journals Noncanonical role of Arabidopsis COP1/SPA complex in repressing BIN2-mediated PIF3 phosphorylation and degradation in darkness

2017 ◽  
Vol 114 (13) ◽  
pp. 3539-3544 ◽  
Author(s):  
Jun-Jie Ling ◽  
Jian Li ◽  
Danmeng Zhu ◽  
Xing Wang Deng
Keyword(s):  
E3 Ligase ◽  
26S Proteasome ◽  
Complex Action ◽  
Precise Control ◽  
Strong Stabilization ◽  
Proteasome Pathway

The E3 ligase CONSTITUTIVELY PHOTOMORPHOGENIC 1 (COP1) has been known to mediate key signaling factors for degradation via the ubiquitin/26S proteasome pathway in both plants and animals. Here, we report a noncanonical function of Arabidopsis COP1, the central repressor of photomorphogenesis, in the form of a COP1/ SUPPRESSOR of phyA-105 (SPA) complex. We show that the COP1/SPA complex associates with and stabilizes PHYTOCHROME INTERACTING FACTOR 3 (PIF3) to repress photomorphogenesis in the dark. We identify the GSK3-like kinase BRASSINOSTEROID-INSENSITIVE 2 (BIN2) as a kinase of PIF3, which induces PIF3 degradation via 26S proteasome during skotomorphogenesis. Mutations on two typical BIN2 phosphorylation motifs of PIF3 lead to a strong stabilization of the protein in the dark. We further show that the COP1/SPA complex promotes PIF3 stability by repressing BIN2 activity. Intriguingly, without affecting BIN2 expression, the COP1/SPA complex modulates BIN2 activity through interfering with BIN2–PIF3 interaction, thereby inhibiting BIN2-mediated PIF3 phosphorylation and degradation. Taken together, our results suggest another paradigm for COP1/SPA complex action in the precise control of skotomorphogenesis.

scholarly journals Spermidine supplementation in rare translation associated disorders

Cell Stress ◽  
2021 ◽  
Vol 5 (3) ◽  
pp. 29-32
Author(s):  
Andreas Zimmermann ◽  
Didac Carmona-Gutierrez ◽  
Frank Madeo
Keyword(s):  
Translation Initiation ◽  
Cell Function ◽  
Immune Cell ◽  
Protein Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Model Organisms ◽  
Immune Cell Function ◽  
Mendelian Disorders

The polyamine spermidine is essential for protein translation in eukaryotes, both as a substrate for the hypusination of the translation initiation factor eIF5A as well as general translational fidelity. Dwindling spermidine levels during aging have been implicated in reduced immune cell function through insufficient eIF5A hypusination, which can be restored by external supplementation. Recent findings characterize a group of novel Mendelian disorders linked to EIF5A missense and nonsense variants that cause protein translation defects. In model organisms that recapitulate these mutations, spermidine supplementation was able to alleviate at least some of the concomitant protein translation defects. Here, we discuss the role of spermidine in protein translation and possible therapeutic avenues for translation-associated disorders.

scholarly journals The E3 ligase MREL57 modulates microtubule stability and stomatal closure in response to ABA

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Liru Dou ◽  
Kaikai He ◽  
Jialin Peng ◽  
Xiangfeng Wang ◽  
Tonglin Mao
Keyword(s):  
Drought Stress ◽  
Stomatal Closure ◽  
E3 Ligase ◽  
26S Proteasome ◽  
Stomatal Movement ◽  
Plant Adaptation ◽  
Ubiquitin E3 Ligase ◽  
Microtubule Stability ◽  
Dependent Pathway

AbstractRegulation of stomatal movement is critical for plant adaptation to environmental stresses. The microtubule cytoskeleton undergoes disassembly, which is critical for stomatal closure in response to abscisic acid (ABA). However, the mechanism underlying this regulation largely remains unclear. Here we show that a ubiquitin-26S proteasome (UPS)-dependent pathway mediates microtubule disassembly and is required for ABA-induced stomatal closure. Moreover, we identify and characterize the ubiquitin E3 ligase MREL57 (MICROTUBULE-RELATED E3 LIGASE57) and the microtubule-stabilizing protein WDL7 (WAVE-DAMPENED2-LIKE7) in Arabidopsis and show that the MREL57-WDL7 module regulates microtubule disassembly to mediate stomatal closure in response to drought stress and ABA treatment. MREL57 interacts with, ubiquitinates and degrades WDL7, and this effect is clearly enhanced by ABA. ABA-induced stomatal closure and microtubule disassembly are significantly suppressed in mrel57 mutants, and these phenotypes can be restored when WDL7 expression is decreased. Our results unravel UPS-dependent mechanisms and the role of an MREL57-WDL7 module in microtubule disassembly and stomatal closure in response to drought stress and ABA.

Abstract 5495: Role of SIRT1 in Smooth Muscle Cell Function and Vascular Remodeling

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Daniel Sedding ◽  
Sabina Vogel ◽  
Harald Tillmanns
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Cell Function ◽  
Model Organisms ◽  
Dependent Manner ◽  
Wild Type ◽  
Vascular Homeostasis

Background: The class III histone deacetylase SIRT1 has been identified as a key regulator of ageing and longevity in model organisms such as S. cerevisiae and C. elegans, which regulates cellular functions such as differentiation, senescence and metabolism. However, the role of SIRT1 for Smooth muscle cell (VSMC) function and vascular homeostasis or during vascular remodelling remains unknown. Methods and Results: Here, we show that SIRT1 is highly expressed in intact blood vessels in vivo as well as in cultured VSMC. Stimulation of SIRT1 activity by either treatment with the SIRT1 activator resveratrol or adenoviral overexpression of wild type SIRT1 but not with an inactive SIRT1 mutant attenuated serum-induced VSMC proliferation in a dose dependent manner in vitro. In contrast, treatment of VSMC with the small molecule weight inhibitors of SIRT1, nicotinamide and sirtinol, augmented the proliferative and migratory activity of VSMC. Consistent with these data, MEF cells isolated from SIRT −/− mice showed an augmented proliferative response to serum stimulation but were also more resistant to starving-induced apoptosis compared to WT-MEF cells. Silencing of endogenous SIRT1 using siRNA resulted in an increased proliferation, migration and apoptosis of VSMC. In vivo, following arterial injury of the mouse femoral artery, SIRT1 was downregulated in the developing neointima. Adenoviral-mediated reconstitution of wild type SIRT1 but not of the inactive SIRT1 mutant prevented neointima formation in vivo. Conclusion: Thus, these data identify SIRT1 as a key regulator of vascular proliferative disease processes and indicate that SIRT1 plays an essential role in proliferative migratory and apoptotic processes which regulate vascular homeostasis and remodeling.

Role of Wnt/PCP pathway on bronchial cell function in Idiopathic Pulmonary Fibrosis

Pneumologie ◽  
2011 ◽  
Vol 65 (12) ◽  
Author(s):  
S Barkha ◽  
M Gegg ◽  
H Lickert ◽  
M Königshoff
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Cell Function

scholarly journals PPM1G promotes the progression of hepatocellular carcinoma via phosphorylation regulation of alternative splicing protein SRSF3

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Dawei Chen ◽  
Zhenguo Zhao ◽  
Lu Chen ◽  
Qinghua Li ◽  
Jixue Zou ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Alternative Splicing ◽  
Protein Function ◽  
Vital Role ◽  
Normal Tissues ◽  
Mechanistic Analysis ◽  
Highly Correlated ◽  
Splicing Patterns

AbstractEmerging evidence has demonstrated that alternative splicing has a vital role in regulating protein function, but how alternative splicing factors can be regulated remains unclear. We showed that the PPM1G, a protein phosphatase, regulated the phosphorylation of SRSF3 in hepatocellular carcinoma (HCC) and contributed to the proliferation, invasion, and metastasis of HCC. PPM1G was highly expressed in HCC tissues compared to adjacent normal tissues, and higher levels of PPM1G were observed in adverse staged HCCs. The higher levels of PPM1G were highly correlated with poor prognosis, which was further validated in the TCGA cohort. The knockdown of PPM1G inhibited the cell growth and invasion of HCC cell lines. Further studies showed that the knockdown of PPM1G inhibited tumor growth in vivo. The mechanistic analysis showed that the PPM1G interacted with proteins related to alternative splicing, including SRSF3. Overexpression of PPM1G promoted the dephosphorylation of SRSF3 and changed the alternative splicing patterns of genes related to the cell cycle, the transcriptional regulation in HCC cells. In addition, we also demonstrated that the promoter of PPM1G was activated by multiple transcription factors and co-activators, including MYC/MAX and EP300, MED1, and ELF1. Our study highlighted the essential role of PPM1G in HCC and shed new light on unveiling the regulation of alternative splicing in malignant transformation.

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