independent functions
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2022 ◽  
Vol 10 (2) ◽  
pp. 01-06
Author(s):  
Frank Mayer

Bacteria possess an EF-Tu-based cytoskeleton.This article presents a short review. A number of questions which are not discussed in the former publications can be asked, such as: all bacteria possess a ribosomal protein synthesis system and, hence, also EF-Tu. EF-Tu is produced in an amount that is higher than the need for a function as translation elogation factor in ribsomal protein synthesis. This article tries to answer the question regarding the surplus of EF-Tu: formation of a "cell-wide web" by self-assembly as a feafure that stabilizes cell integrity. An additional question can be asked: what is the origin of this bacterial cytoskeleton? This article contains a speculation on this topic. A third question regards the'ntteructjon of ribosomes in the process of protemsynthesis: does the EF-Tu protein move to the ribosome, or does the ribosome move to the EF-Tu intergated in a fibril of the bacterial cytoskeleton? The former publication depicts electron micrographs which show colocalizatton of botth entities. EF-Tu is an example for aprotein with two independent functions: participation in the ribosomal protein synthesis as a kanslation elongation factor, and component of a bacterial cytoskeleton. This situation can open up a discussion ofthe sequence of events and states of early cells during evolution.


Author(s):  
Satoshi Minami ◽  
Shuhei Nakamura ◽  
Tamotsu Yoshimori

Autophagy is a conserved cellular degradation system that maintains intracellular homeostasis. Cytoplasmic components are engulfed into double-membrane vesicles called autophagosomes, which fuse with lysosomes, and resulting in the degradation of sequestered materials. Recently, a close association between autophagy and the pathogenesis of metabolic diseases and ageing has become apparent: autophagy is dysregulated during metabolic diseases and ageing; dysregulation of autophagy is intimately associated with the pathophysiology. Rubicon (Run domain Beclin-1 interacting and cysteine-rich containing protein) has been identified as a Beclin-1 associated protein. Notably, Rubicon is one of few negative regulators of autophagy whereas many autophagy-related genes are positive regulators of autophagy. Rubicon also has autophagy-independent functions including phagocytosis and endocytosis. In this mini-review, we focus on the various roles of Rubicon in different organs in the settings of metabolic diseases and ageing, and discuss its potential role as a promising therapeutic target.


Biomolecules ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 59
Author(s):  
Karla N. Valenzuela-Valderas ◽  
Gabriel Moreno-Hagelsieb ◽  
John R. Rohde ◽  
Rafael A. Garduño

Group I chaperonins are a highly conserved family of essential proteins that self-assemble into molecular nanoboxes that mediate the folding of cytoplasmic proteins in bacteria and organelles. GroEL, the chaperonin of Escherichia coli, is the archetype of the family. Protein folding-independent functions have been described for numerous chaperonins, including HtpB, the chaperonin of the bacterial pathogen Legionella pneumophila. Several protein folding-independent functions attributed to HtpB are not shared by GroEL, suggesting that differences in the amino acid (aa) sequence between these two proteins could correlate with functional differences. GroEL and HtpB differ in 137 scattered aa positions. Using the Evolutionary Trace (ET) bioinformatics method, site-directed mutagenesis, and a functional reporter test based upon a yeast-two-hybrid interaction with the eukaryotic protein ECM29, it was determined that out of those 137 aa, ten (M68, M212, S236, K298, N507 and the cluster AEHKD in positions 471-475) were involved in the interaction of HtpB with ECM29. GroEL was completely unable to interact with ECM29, but when GroEL was modified at those 10 aa positions, to display the HtpB aa, it acquired a weak ability to interact with ECM29. This constitutes proof of concept that the unique functional abilities of HtpB can be mapped to specific aa positions.


Author(s):  
A. V. Ivashkevich ◽  
E. M. Ovsiyuk ◽  
V. V. Kisel ◽  
V. M. Red’kov

Relativistic system for a vector-bispinior describing a massless spin 3/2 field is studied in the spherical coordinates of Minkowski space. Presentation of the equation with the use of the covariant Levi-Civita tensor exhibits existence of the gauge solutions in the form of the covariant 4-gradient of an arbitrary bispinor. Substitution for 16-component field function is based on the use of Wigner functions, it assumes diagonalization of the operators of energy, square and third projection of the total angular momentum, and space reflection. We derive radial system for eight independent functions. General structure of the spherical gauge solutions is specified, and it is demonstrated that the gauge radial functions satisfy the derived system. It is proved that the general system reduces to two couples of independent 2-nd order and nonhomogeneous differential equations, their particular solutions may be found with the use of the gauge solutions. The corresponding homogeneous equations have one the same form, they have three regular singularities and one irregular of the rank 2. Frobenius types solutions for this equation have been constructed, and the structure of the involved power series with 4-term recurrent relations sre studied. Six remaining radial functions may be straightforwardly found by means of the simple algebraic relations. Thus, we have constructed two types of solutions with opposite parities which do not contain gauge constituents.


2021 ◽  
Author(s):  
Aikaterini Mechtidou ◽  
Franziska Greulich ◽  
Benjamin A Strickland ◽  
Celine Jouffe ◽  
Filippo M. Cernilogar ◽  
...  

Glucocorticoids (such as Dexamethasone) are commonly used immunomodulatory drugs with potent anti-inflammatory effects, whose mechanisms of action remain incompletely understood. They bind to the Glucocorticoid Receptor (GR), a nuclear hormone receptor that acts as a transcription factor to directly control the expression of inflammatory genes. To elucidate the complex molecular mechanisms employed by GR during the suppression of innate immune responses, we have performed proteomics, ChIP-seq, ATAC-seq, RNA-seq and bioinformatics together with genetic and pharmacological loss of function studies in primary mouse macrophages. We found that GR interacts with the ATP-dependent SWI/SNF chromatin remodeling complex to regulate a specific subset of target genes. Here we show that the central catalytic subunit BRG1 is required not only for the transcriptional activation of classical GR target genes such as Fkbp5 or Klf9, but also for the transcriptional repression of cytokines and chemokines such as Ccl2, Cxcl10 or Il1a. We demonstrate that loss of BRG1 activity leads to reduced histone deacetylase (HDAC) function, and consequently increased histone acetylation, at these repressive GR binding sites. Altogether, our findings suggest that GR interacts with BRG1 to assemble a functional co-repressor complex at a defined fraction of macrophage cis-regulatory elements. These results may indicate additional non-classical, remodeling-independent functions of the SWI/SNF complex and may have implications for the development of future immunomodulatory therapies.


Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3463
Author(s):  
Shilpa Patil ◽  
Teresa Forster ◽  
Kristina Reutlinger ◽  
Waltraut Kopp ◽  
Lennart Versemann ◽  
...  

Background: The Nuclear Factor of Activated T-cells 1 (NFATc1) transcription factor and the methyltransferase Enhancer of Zeste Homolog 2 (EZH2) significantly contribute to the aggressive phenotype of pancreatic ductal adenocarcinoma (PDAC). Herein, we aimed at dissecting the mechanistic background of their interplay in PDAC progression. Methods: NFATc1 and EZH2 mRNA and protein expression and complex formation were determined in transgenic PDAC models and human PDAC specimens. NFATc1 binding on the Ezh2 gene and the consequences of perturbed NFATc1 expression on Ezh2 transcription were explored by Chromatin Immunoprecipitation (ChIP) and upon transgenic or siRNA-mediated interference with NFATc1 expression, respectively. Integrative analyses of RNA- and ChIP-seq data was performed to explore NFATc1-/EZH2-dependent gene signatures. Results: NFATc1 targets the Ezh2 gene for transcriptional activation and biochemically interacts with the methyltransferase in murine and human PDAC. Surprisingly, our genome-wide binding and expression analyses do not link the protein complex to joint gene regulation. In contrast, our findings provide evidence for chromatin-independent functions of the NFATc1:EZH2 complex and reveal posttranslational EZH2 phosphorylation at serine 21 as a prerequisite for robust complex formation. Conclusion: Our findings disclose a previously unknown NFATc1-EZH2 axis operational in the pancreas and provide mechanistic insights into the conditions fostering NFATc1:EZH2 complex formation in PDAC.


Author(s):  
Lisa Scarfe ◽  
Gillian M. Mackie ◽  
Kendle M. Maslowski

The gut relies on the complex interaction between epithelial, stromal and immune cells to maintain gut health in the face of food particles and pathogens. Innate sensing by the intestinal epithelium is critical for maintaining epithelial barrier function and also orchestrating mucosal immune responses. Numerous innate pattern recognition receptors (PRRs) are involved in such sensing. In recent years, several Nucleotide-binding-domain and Leucine-rich repeat-containing receptors (NLRs) have been found to partake in pathogen or damage sensing while also being implicated in gut pathologies, such as colitis and colorectal cancer (CRC). Here, we discuss the current literature focusing on NLR family apoptosis inhibitory proteins (NAIPs) and other NLRs that have non-inflammasome roles in the gut. The mechanisms behind NLR-mediated protection often converges on similar signalling pathways, such as STAT3, MAPK and NFκB. Further understanding of how these NLRs contribute to the maintenance of gut homeostasis will be important for understanding gut pathologies and developing new therapies.


2021 ◽  
Vol 118 (47) ◽  
pp. e2112258118
Author(s):  
HyeonJoo Cheon ◽  
Elise G. Holvey-Bates ◽  
Daniel J. McGrail ◽  
George R. Stark

Programmed death ligand 1 (PD-L1), an immune-checkpoint protein expressed on cancer cells, also functions independently of the immune system. We found that PD-L1 inhibits the killing of cancer cells in response to DNA damage in an immune-independent manner by suppressing their acute response to type I interferon (IFN; IFN-I). In addition, PD-L1 plays a critical role in sustaining high levels of constitutive expression in cancer cells of a subset of IFN-induced genes, the IFN-related DNA damage resistance signature (IRDS) which, paradoxically, protects cancer cells. The cyclic GMP-AMP synthase-stimulator of the IFN genes (cGAS-STING) pathway is constitutively activated in a subset of cancer cells in the presence of high levels of PD-L1, thus leading to a constitutive, low level of IFN-β expression, which in turn increases IRDS expression. The constitutive low level of IFN-β expression is critical for the survival of cancer cells addicted to self-produced IFN-β. Our study reveals immune-independent functions of PD-L1 that inhibit cytotoxic acute responses to IFN-I and promote protective IRDS expression by supporting protective chronic IFN-I responses, both of which enhance the resistance of cancer cells to DNA damage.


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