scholarly journals Reduction of insulin/IGF-1 receptor rejuvenates immunity via positive feedback circuit

2019 ◽  
Author(s):  
Yujin Lee ◽  
Dae-Eun Jeong ◽  
Wooseon Hwang ◽  
Seokjin Ham ◽  
Hae-Eun H. Park ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Positive Feedback ◽  
Feedback Mechanism ◽  
Mitogen Activated Protein Kinase ◽  
Bzip Transcription Factor ◽  
C Elegans ◽  
Positive Feedback Circuit ◽  
Mitogen Activated Protein ◽  
Positive Feedback Mechanism ◽  
Transcription Factor 1

SummaryImmunosenescence is considered an inevitable decline in immune function during aging. Here we show that genetic inhibition of the DAF-2/insulin/IGF-1 receptor drastically delays immunosenescence and rejuvenates immunity in C. elegans. We find that p38 mitogen-activated protein kinase 1 (PMK-1), a key determinant of immunosenescence, is dispensable for this rejuvenated immunity. Instead, we demonstrate that longevity-promoting DAF-16/FOXO and heat-shock transcription factor 1 (HSF-1) increase immunocompetence in old daf-2(-) animals. The upregulation of DAF-16/FOXO and HSF-1 decreases the expression of the zip-10/bZIP transcription factor, which in turn downregulates INS-7, an agonistic insulin-like peptide, resulting in further reduction of insulin/IGF-1 signaling (IIS). Thus, reduced IIS bypasses immunosenescence and rejuvenates immunity via the upregulation of anti-aging transcription factors that modulate an endocrine insulin-like peptide through a positive feedback mechanism. Because many functions of IIS are conserved across phyla, our study may lead to the development of strategies for human immune rejuvenation.

scholarly journals Reduced insulin/IGF1 signaling prevents immune aging via ZIP-10/bZIP–mediated feedforward loop

2021 ◽  
Vol 220 (5) ◽  
Author(s):  
Yujin Lee ◽  
Yoonji Jung ◽  
Dae-Eun Jeong ◽  
Wooseon Hwang ◽  
Seokjin Ham ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Mitogen Activated Protein Kinase ◽  
Bzip Transcription Factor ◽  
Immune Functions ◽  
C Elegans ◽  
Feedforward Loop ◽  
Mitogen Activated Protein ◽  
Living Organisms ◽  
Transcription Factor 1

A hallmark of aging is immunosenescence, a decline in immune functions, which appeared to be inevitable in living organisms, including Caenorhabditis elegans. Here, we show that genetic inhibition of the DAF-2/insulin/IGF-1 receptor drastically enhances immunocompetence in old age in C. elegans. We demonstrate that longevity-promoting DAF-16/FOXO and heat-shock transcription factor 1 (HSF-1) increase immunocompetence in old daf-2(−) animals. In contrast, p38 mitogen-activated protein kinase 1 (PMK-1), a key determinant of immunity, is only partially required for this rejuvenated immunity. The up-regulation of DAF-16/FOXO and HSF-1 decreases the expression of the zip-10/bZIP transcription factor, which in turn down-regulates INS-7, an agonistic insulin-like peptide, resulting in further reduction of insulin/IGF-1 signaling (IIS). Thus, reduced IIS prevents immune aging via the up-regulation of anti-aging transcription factors that modulate an endocrine insulin-like peptide through a feedforward mechanism. Because many functions of IIS are conserved across phyla, our study may lead to the development of strategies against immune aging in humans.

scholarly journals A novel positive feedback mechanism of ABI5 phosphorylation by mitogen activated protein kinase-3 regulates ABA signaling in Arabidopsis

2021 ◽  
Author(s):  
Prakash Kumar Bhagat ◽  
Deepanjali Verma ◽  
Neetu Verma ◽  
Alok Krishna Sinha
Keyword(s):  
Seed Germination ◽  
Map Kinases ◽  
Feedback Mechanism ◽  
Floral Transition ◽  
Mitogen Activated Protein Kinase ◽  
Aba Signaling ◽  
Regulatory Pathways ◽  
Mitogen Activated Protein ◽  
Kinase Cascade ◽  
Positive Feedback Mechanism

AbstractSeed germination is the crucial physiological process regulated by both environmental and endogenous phytohormones. ABA negatively regulates seed germination, post-germination growth and floral transition, however, the cross talk between multiple regulatory pathways are still unclear. Here, we show that ABA activates two MAP kinases, AtMPK3/AtMPK6 and selectively regulates the transcript of AtMPK3 through ABI5, a master regulator of ABA signaling. As a feedback loop, AtMPK3 interacts and phosphorylates ABI5 at the serine-314 position. ABI5 phosphorylation by MAP kinases positively regulates ABI5 nuclear localization and negatively regulates its dimerization. Subcellular localization of ABI5 phospho-null protein further suggests the role of phosphorylation in regulation of its cytoplasmic stability and its nuclear dimerization. Overexpression of phosphor-null ABI5 in abi5-8 mutant restored the ABA sensitivity during seed germination and delayed the floral transition as compared to phospho-mimic ABI5. Additionally, overexpression of constitutive phosphorylated ABI5 in abi5-8 mutants suggest that phosphorylation makes ABI5 partially inactive. Furthermore, phospho-null ABI5 plants showed drought sensitive phenotype whereas, mpk3, mkk4, mkk5, abi5-8 and phosphor-mimic plants showed drought tolerant phenotype. Our findings present a new insight between MAP kinase cascade and ABA signaling which collectively regulates the ABA response through ABI5 phosphorylation.

scholarly journals Model-driven experimental design identifies counter-acting feedback regulation in the osmotic stress response of yeast

2020 ◽  
Author(s):  
Sara Kimiko Suzuki ◽  
Beverly Errede ◽  
Henrik G. Dohlman ◽  
Timothy C. Elston
Keyword(s):  
Mathematical Models ◽  
Positive Feedback ◽  
Feedback Regulation ◽  
Feedback Mechanism ◽  
Model Driven ◽  
Osmotic Stress Response ◽  
Mitogen Activated Protein ◽  
Mapk Phosphatases ◽  
Positive Feedback Mechanism

AbstractCells rely on mitogen-activated protein kinases (MAPKs) to survive environmental stress. In yeast, activation of the MAPK Hog1 is known to mediate the response to high osmotic conditions. Recent studies of Hog1 revealed that its temporal activity is subject to both negative and positive feedback regulation, yet the mechanisms of feedback remain unclear. By designing mathematical models of increasing complexity for the Hog1 MAPK cascade, we identified pathway circuitry sufficient to capture Hog1 dynamics observed in vivo. We used these models to optimize experimental designs for distinguishing potential feedback loops. Performing experiments based on these models revealed mutual inhibition between Hog1 and its phosphatases as the likely positive feedback mechanism underlying switch-like, dose-dependent MAPK activation. Importantly, our findings reveal a new signaling function for MAPK phosphatases. More broadly, they demonstrate the value using mathematical models to infer targets of feedback regulation in signaling pathways.

scholarly journals Robust designation of meiotic crossover sites by CDK-2 through phosphorylation of the MutSγ complex

2021 ◽  
Author(s):  
Jocelyn Haversat ◽  
Alexander Woglar ◽  
Kayla Klatt ◽  
Chantal C. Akerib ◽  
Victoria Roberts ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Feedback Mechanism ◽  
Double Strand Breaks ◽  
Cyclin Dependent Kinase ◽  
Wild Type ◽  
Strand Breaks ◽  
Homologous Chromosomes ◽  
C Elegans ◽  
Meiotic Crossover ◽  
Positive Feedback Mechanism

SUMMARYCrossover formation is essential for proper segregation of homologous chromosomes during meiosis. Here we show that C. elegans Cyclin-dependent kinase 2 (CDK-2) forms a complex with cyclin-like protein COSA-1 and supports crossover formation by promoting conversion of meiotic double-strand breaks (DSBs) into crossover-specific recombination intermediates. Further, we identify MutSγ component MSH-5 as a CDK-2 phosphorylation target. MSH-5 has a disordered C-terminal tail that contains 13 potential CDK phosphosites and is required to concentrate crossover-promoting proteins at recombination sites. Phosphorylation of the MSH-5 tail appears dispensable in a wild- type background, but when MutSγ activity is partially compromised, crossover formation and retention of CDK-2/COSA-1 at recombination sites are exquisitely sensitive to phosphosite loss. Our data support a model in which robustness of crossover designation reflects a positive feedback mechanism involving CDK-2-mediated phosphorylation and scaffold-like properties of the MSH-5 C-terminal tail, features that combine to promote full recruitment and activity of crossover-promoting complexes.

scholarly journals A novel family of dehydrin-like proteins is involved in stress response in the human fungal pathogenAspergillus fumigatus

2011 ◽  
Vol 22 (11) ◽  
pp. 1896-1906 ◽  
Author(s):  
Joanne Wong Sak Hoi ◽  
Claude Lamarre ◽  
Rémi Beau ◽  
Isabelle Meneau ◽  
Adokiye Berepiki ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Protein Kinase ◽  
Stress Responses ◽  
Fluorescent Protein ◽  
Mapk Pathway ◽  
Experimental Models ◽  
Mitogen Activated Protein Kinase ◽  
Bzip Transcription Factor ◽  
Mitogen Activated Protein ◽  
Protective Proteins

 During a search for genes controlling conidial dormancy in Aspergillus fumigatus, two dehydrin-like genes, DprA and DprB, were identified. The deduced proteins had repeated stretches of 23 amino acids that contained a conserved dehydrin-like protein (DPR) motif. Disrupted DprAΔ mutants were hypersensitive to oxidative stress and to phagocytic killing, whereas DprBΔ mutants were impaired in osmotic and pH stress responses. However, no effect was observed on their pathogenicity in our experimental models of invasive aspergillosis. Molecular dissection of the signaling pathways acting upstream showed that expression of DprA was dependent on the stress-activated kinase SakA and the cyclic AMP-protein kinase A (cAMP-PKA) pathways, which activate the bZIP transcription factor AtfA, while expression of DprB was dependent on the SakA mitogen-activated protein kinase (MAPK) pathway, and the zinc finger transcription factor PacC. Fluorescent protein fusions showed that both proteins were associated with peroxisomes and the cytosol. Accordingly, DprA and DprB were important for peroxisome function. Our findings reveal a novel family of stress-protective proteins in A. fumigatus and, potentially, in filamentous ascomycetes.

scholarly journals Activation of a Novel Transcription Factor through Phosphorylation by WIPK, a Wound-Induced Mitogen-Activated Protein Kinase in Tobacco Plants

2005 ◽  
Vol 139 (1) ◽  
pp. 127-137 ◽  
Author(s):  
Yun-Kiam Yap ◽  
Yutaka Kodama ◽  
Frank Waller ◽  
Kwi Mi Chung ◽  
Hirokazu Ueda ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Tobacco Plants ◽  
Mitogen Activated Protein

scholarly journals Mitogen-Activated Protein Kinase Feedback Phosphorylation Regulates MEK1 Complex Formation and Activation during Cellular Adhesion

2004 ◽  
Vol 24 (6) ◽  
pp. 2308-2317 ◽  
Author(s):  
Scott T. Eblen ◽  
Jill K. Slack-Davis ◽  
Adel Tarcsafalvi ◽  
J. Thomas Parsons ◽  
Michael J. Weber ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Complex Formation ◽  
Feedback System ◽  
Cellular Adhesion ◽  
Feedback Mechanism ◽  
Mitogen Activated Protein Kinase ◽  
Integrin Signaling ◽  
Mitogen Activated Protein ◽  
P21 Activated Kinase

ABSTRACT Cell adhesion and spreading depend on activation of mitogen-activated kinase, which in turn is regulated both by growth factor and integrin signaling. Growth factors, such as epidermal growth factor, are capable of activating Ras and Raf, but integrin signaling is required to couple Raf to MEK and MEK to extracellular signal-regulated protein kinase (ERK). It was previously shown that Rac-p21-activated kinase (PAK) signaling regulated the physical association of MEK1 with ERK2 through phosphorylation sites in the proline-rich sequence (PRS) of MEK1. It was also shown that activation of MEK1 and ERK by integrins depends on PAK phosphorylation of S298 in the PRS. Here we report a novel MEK1-specific regulatory feedback mechanism that provides a means by which activated ERK can terminate continued PAK phosphorylation of MEK1. Activated ERK can phosphorylate T292 in the PRS, and this blocks the ability of PAK to phosphorylate S298 and of Rac-PAK signaling to enhance MEK1-ERK complex formation. Preventing ERK feedback phosphorylation on T292 during cellular adhesion prolonged phosphorylation of S298 by PAK and phosphorylation of S218 and S222, the MEK1 activating sites. We propose that activation of ERK during adhesion creates a feedback system in which ERK phosphorylates MEK1 on T292, and this in turn blocks additional S298 phosphorylation in response to integrin signaling.

Sign in / Sign up

Export Citation Format

Share Document