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2022 ◽  
Author(s):  
Grant Dewson ◽  
Alan Shuai Huang ◽  
Hui San Chin ◽  
Boris Reljic ◽  
Tirta M Djajawi ◽  
...  

Intrinsic apoptosis is principally governed by the BCL-2 family of proteins, but some non-BCL-2 proteins are also critical to control this process. To identify novel apoptosis regulators, we performed a genome-wide CRISPR-Cas9 library screen, and identified the mitochondrial E3 ubiquitin ligase MARCHF5/MITOL/RNF153 as an important regulator of BAK apoptotic function. Deleting MARCHF5 in diverse cell lines dependent on BAK conferred profound resistance to BH3-mimetic drugs. The loss of MARCHF5 or its E3 ubiquitin ligase activity surprisingly drove BAK to adopt an activated conformation, with resistance to BH3-mimetics afforded by the formation of inhibitory complexes with pro-survival proteins MCL-1 and BCL-XL. Importantly, these changes to BAK conformation and pro-survival association occurred independently of BH3-only proteins and influence on pro-survival proteins. This study identifies a new mechanism by which MARCHF5 regulates apoptotic cell death and provides new insight into how cancer cells respond to BH3-mimetic drugs. These data also highlight the emerging role of ubiquitin signalling in apoptosis that may be exploited therapeutically.


2021 ◽  
Vol 8 ◽  
Author(s):  
Lin Cui ◽  
Qiong Zhang ◽  
Yao Huang ◽  
Lei Yang ◽  
Junhui Zhang ◽  
...  

Lysosomal dysfunction has been found in many pathological conditions, and methods to improve lysosomal function have been reported to be protective against infarcted hearts. However, the mechanisms underlying lysosomal dysfunction caused by ischemic injury are far less well-established. The retromer complex is implicated in the trafficking of cation-independent mannose 6-phosphate receptor (CI-MPR), which is an important protein tag for the proper transport of lysosomal contents and therefore is important for the maintenance of lysosomal function. In this study, we found that the function of retrograde transport in cardiomyocytes was impaired with ischemia/hypoxia (I/H) treatment, which resulted in a decrease in CI-MPR and an abnormal distribution of lysosomal cathepsins. I/H treatment caused a reduction in TBC1D5 and a blockade of the Rab7 membrane cycle, which impeded retromer binding to microtubules and motor proteins, resulting in an impairment of retrograde transport and a decrease in CI-MPR. We also established that TBC1D5 was an important regulator of the distribution of lysosomal cathepsins. Our findings shed light on the regulatory role of retromer in ischemic injury and uncover the regulatory mechanism of TBC1D5 over retromer.


Antioxidants ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 12
Author(s):  
Mike Aoun ◽  
Xiaojie Cai ◽  
Bingze Xu ◽  
Gonzalo Fernandez Lahore ◽  
Michael Yi Bonner ◽  
...  

Animal models for complex diseases are needed to position and analyze the function of interacting genes. Previous positional cloning identified Ncf1 and Clec4b to be major regulators of arthritis models in rats. Here, we investigate epistasis between Ncf1 and Clec4b, two major regulators of arthritis in rats. We find that Clec4b and Ncf1 exert an additive effect on arthritis given by their joint ability to regulate neutrophils. Both genes are highly expressed in neutrophils, together regulating neutrophil availability and their capacity to generate reactive oxygen species. Using a glycan array, we identify key ligands of Clec4b and demonstrate that Clec4b-specific stimulation triggers neutrophils into oxidative burst. Our observations highlight Clec4b as an important regulator of neutrophils and demonstrate how epistatic interactions affect the susceptibility to, and severity of, autoimmune arthritis.


2021 ◽  
Vol 23 (1) ◽  
pp. 90
Author(s):  
Valeria Domenica Zingale ◽  
Agnese Gugliandolo ◽  
Emanuela Mazzon

MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression at the post-transcriptional level and that play an important role in many cellular processes, including modulation of inflammation. MiRNAs are present in high concentrations in the central nervous system (CNS) and are spatially and temporally expressed in a specific way. Therefore, an imbalance in the expression pattern of these small molecules can be involved in the development of neurological diseases. Generally, CNS responds to damage or disease through the activation of an inflammatory response, but many neurological disorders are characterized by uncontrolled neuroinflammation. Many studies support the involvement of miRNAs in the activation or inhibition of inflammatory signaling and in the promotion of uncontrolled neuroinflammation with pathological consequences. MiR-155 is a pro-inflammatory mediator of the CNS and plays an important regulatory role. The purpose of this review is to summarize how miR-155 is regulated and the pathological consequences of its deregulation during neuroinflammatory disorders, including multiple sclerosis, Alzheimer’s disease and other neuroinflammatory disorders. Modulation of miRNAs’ expression could be used as a therapeutic strategy in the treatment of pathological neuroinflammation.


Eos ◽  
2021 ◽  
Vol 102 ◽  
Author(s):  
Morgan Rehnberg

A new model helps shed light on residue mulch, an important regulator of surface soil conditions.


2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Robert Moore ◽  
Kaice LaFavers ◽  
Tarek El-Ashkar

Background and Hypothesis:  Tamm-Horsfall protein (THP) is an important regulator of urinary and systemic homeostasis expressed exclusively in the kidney. Complete knockout of THP has been shown to lead to systemic oxidative damage in a mouse model. To develop a more clinically relevant model, we generated a tamoxifen inducible knockout/heterozygote mouse using the Cre/Lox system. We hypothesize that inducing a heterozygous state would increase levels of oxidative damage in mice.  Methods:  Experimental mice were generated by breeding THPfl/fl mice with ROSACreERT2/CreERT2 mice to develop the inducible heterozygote THPfl/+RosaCreERT2. These mice, along with controls (THPfl/fl) were treated with daily intraperitoneal injections of 75 mg/kg tamoxifen for 5 days. Serum samples were obtained from mice at baseline and 1, 2 and 3 weeks from the first injection, while kidneys were harvested at 1 or 3 weeks. PCR of kidney genomic DNA demonstrated excision of the floxed allele in mice expressing Cre-ERT2.  Western Blot analysis of kidney lysates was used to measure kidney THP, while circulating THP was measured by ELISA. Oxidative DNA damage was measured in the kidney and circulation by ELISA.  Results:  Though kidney THP levels decreased in mice expressing Cre-ERT2, circulating levels of THP remained stable, with evidence of transient increases at 1 or 2 weeks for most animals. Mice expressing Cre-ERT2 had significantly increased oxidative DNA damage within the kidney and there was a trend toward increased oxidative DNA damage in the serum, though larger sample sizes are required to verify this finding.  Conclusion:  Despite decreased THP in the kidney, mice maintained normal levels of circulating THP. However, higher levels of oxidative damage were found in both the kidney and circulation. Together, these results suggest that THP levels in the serum are tightly controlled and that an acute loss of THP leads to rapid increases in oxidative damage. 


2021 ◽  
Author(s):  
Dimitar Plamenov Petrov ◽  
Steffen Kaiser ◽  
Stefanie Kaiser ◽  
Kirsten Jung

mRNA methylation is an important regulator of many physiological processes in eukaryotes but has not been studied in depth in prokaryotes. In contrast to the large number of eukaryotic mRNA modifications that have been described, N6-methyladenosine (m6A) is the only modification of bacterial mRNA identified to date. Here, we used a gel electrophoresis-based RNA separation method and quantitatively analyzed the mRNA-specific modification profile of Escherichia coli using mass spectrometry. In addition to m6A, we provide evidence for the presence of 7-methylguanosine (m7G), and we found first hints for 5-methylcytidine (m5C), N6,N6-dimethyladenosine (m6,6A), 1-methylguanosine (m1G), 5-methyluridine (m5U), and pseudouridine (Ψ) in the mRNA of E. coli, which implies that E. coli has a complex mRNA modification pattern. Furthermore, we observed changes in the abundance of some mRNA modifications during the transition of E. coli from the exponential growth to the stationary phase as well as upon exposure to stress. This study reveals a previously underestimated level of regulation between transcription and translation in bacteria.


2021 ◽  
Author(s):  
N Kislev ◽  
L Mor-Yossef Moldovan ◽  
R Barak ◽  
M Egozi ◽  
D Benayahu

AbstractAdipocyte differentiation is dependent on cytoskeletal remodeling processes that determine and maintain cellular shape and function. In turn, cytoskeletal proteins contribute to the filament-based network responsible for controlling adipocyte’s shape and promoting the intracellular trafficking of key cellular components. Currently, our understanding of these mechanisms remains incomplete. In this study, we identified the non-muscle myosin 10 (MYH10) as an important regulator of adipogenesis and adipocyte function through its interaction with the insulin dependent, Glucose transporter 4 (GLUT4). MYH10 depletion in preadipocytes resulted in impaired adipogenesis, with knockdown cells exhibiting disrupted morphology and reduced molecular adipogenic signals. MYH10 was shown to be in complex with GLUT4 in adipocytes, an interaction regulated by insulin induction. The missing adipogenic capacity of MYH10-KD cells was restored when they uptook GLUT4 vesicles up from neighbor wild-type cells in a co-culture system. Our results provide the first demonstration that MYH10 interacts with GLUT4 in cells and adipose tissue through the insulin pathway. The signaling cascade is regulated by the protein kinase C ζ (PKCζ), which interacts with MYH10 to modify the localization and interaction of both GLUT4 and MYH10 in adipocytes as PKCζ inhibition resulted in reduced GLUT4 and MYH10 translocation and interactions. Overall, our study establishes MYH10 as an essential regulator of GLUT4 translocation, affecting both adipogenesis and adipocyte function, highlighting its importance in future cytoskeleton-based studies in adipocytes.


Antioxidants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1951
Author(s):  
Elena G. Novoselova ◽  
Mars G. Sharapov ◽  
Sergey M. Lunin ◽  
Svetlana B. Parfenyuk ◽  
Maxim O. Khrenov ◽  
...  

Although many different classes of antioxidants have been evaluated as radioprotectors, none of them are in widespread clinical use because of their low efficiency. The goal of our study was to evaluate the potential of the antioxidant protein peroxiredoxin 6 (Prdx6) to increase the radioresistance of 3T3 fibroblasts when Prdx6 was applied after exposure to 6 Gy X-ray. In the present study, we analyzed the mRNA expression profiles of genes associated with proliferation, apoptosis, cellular stress, senescence, and the production of corresponding proteins from biological samples after exposure of 3T3 cells to X-ray radiation and application of Prdx6. Our results suggested that Prdx6 treatment normalized p53 and NF-κB/p65 expression, p21 levels, DNA repair-associated genes (XRCC4, XRCC5, H2AX, Apex1), TLR expression, cytokine production (TNF-α and IL-6), and apoptosis, as evidenced by decreased caspase 3 level in irradiated 3T3 cells. In addition, Prdx6 treatment reduced senescence, as evidenced by the decreased percentage of SA-β-Gal positive cells in cultured 3T3 fibroblasts. Importantly, the activity of the NRF2 gene, an important regulator of the antioxidant cellular machinery, was completely suppressed by irradiation but was restored by post-irradiation Prdx6 treatment. These data support the radioprotective therapeutic efficacy of Prdx6.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Dimitra Zotos ◽  
Isaak Quast ◽  
Connie S. N. Li-Wai-Suen ◽  
Craig I. McKenzie ◽  
Marcus J. Robinson ◽  
...  

AbstractHumoral immune responses require germinal centres (GC) for antibody affinity maturation. Within GC, B cell proliferation and mutation are segregated from affinity-based positive selection in the dark zone (DZ) and light zone (LZ) substructures, respectively. While IL-21 is known to be important in affinity maturation and GC maintenance, here we show it is required for both establishing normal zone representation and preventing the accumulation of cells in the G1 cell cycle stage in the GC LZ. Cell cycle progression of DZ B cells is unaffected by IL-21 availability, as is the zone phenotype of the most highly proliferative GC B cells. Collectively, this study characterises the development of GC zones as a function of time and B cell proliferation and identifies IL-21 as an important regulator of these processes. These data help explain the requirement for IL-21 in normal antibody affinity maturation.


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