scholarly journals AXIN-AMPK signaling: Implications for healthy aging

F1000Research ◽  
2021 ◽  
Vol 10 ◽  
pp. 1259
Author(s):  
Avijit Mallick ◽  
Bhagwati P. Gupta
Keyword(s):  
Muscle Function ◽  
Healthy Aging ◽  
Effector Proteins ◽  
Scaffolding Protein ◽  
Biological Processes ◽  
Ampk Signaling ◽  
Cellular Events ◽  
Muscle Aging ◽  
Energy Sensor ◽  
Muscle Health

The energy sensor AMP kinase (AMPK) and the master scaffolding protein, AXIN, are two major regulators of biological processes in metazoans. AXIN-dependent regulation of AMPK activation plays a crucial role in maintaining metabolic homeostasis during glucose-deprived and energy-stressed conditions. The two proteins are also required for muscle function. While studies have refined our knowledge of various cellular events that promote the formation of AXIN-AMPK complexes and the involvement of effector proteins, more work is needed to understand precisely how the pathway is regulated in response to various forms of stress. In this review, we discuss recent data on AXIN and AMPK interaction and its role in physiological changes leading to improved muscle health and an extension of lifespan. We argue that AXIN-AMPK signaling plays an essential role in maintaining muscle function and manipulating the pathway in a tissue-specific manner could delay muscle aging. Therefore, research on understanding the factors that regulate AXIN-AMPK signaling holds the potential for developing novel therapeutics to slow down or revert the age-associated decline in muscle function, thereby extending the healthspan of animals.

scholarly journals Axin-mediated regulation of lifespan and muscle health in C. elegans involves AMPK-FOXO signaling

2020 ◽  
Author(s):  
Avijit Mallick ◽  
Ayush Ranawade ◽  
Bhagwati P Gupta
Keyword(s):  
Muscle Function ◽  
Significant Risk ◽  
Significant Risk Factor ◽  
Mitochondrial Morphology ◽  
Dependent Manner ◽  
C Elegans ◽  
Muscle Aging ◽  
Muscle Health ◽  
Multiple Signaling

SUMMARYAging is a significant risk factor for several diseases. Studies have uncovered multiple signaling pathways that modulate the process of aging including the Insulin/IGF-1 signaling (IIS). In C. elegans the key regulator of IIS is DAF-16/FOXO whose activity is regulated by phosphorylation. A major kinase involved in DAF-16-mediated lifespan extension is the AMPK catalytic subunit homolog, AAK-2. In this study, we demonstrate a novel role of PRY-1/Axin in AAK-2 activation to regulate DAF-16 function. The pry-1 transcriptome contains many genes associated with aging and muscle function. Consistent with this, pry-1 is strongly expressed in muscles and muscle-specific overexpression of pry-1 extends the lifespan, delays muscle aging, and improves mitochondrial morphology in DAF-16-dependent manner. Furthermore, PRY-1 is necessary for AAK-2 phosphorylation. Together, our data demonstrate a crucial role of PRY-1 in maintaining the lifespan and muscle health. Since muscle health declines with age, our study offers new possibilities to manipulate Axin function to delay muscle aging and improve lifespan.

scholarly journals Regulatory Roles of PINK1-Parkin and AMPK in Ubiquitin-Dependent Skeletal Muscle Mitophagy

2020 ◽  
Vol 11 ◽  
Author(s):  
Alex P. Seabright ◽  
Yu-Chiang Lai
Keyword(s):  
Skeletal Muscle ◽  
Healthy Aging ◽  
Molecular Mechanisms ◽  
Mitochondrial Fission ◽  
Muscle Cells ◽  
Critical Question ◽  
Ampk Signaling ◽  
Age Related ◽  
Muscle Health ◽  
Amp Activated Protein Kinase

The selective removal of damaged mitochondria, also known as mitophagy, is an important mechanism that regulates mitochondrial quality control. Evidence suggests that mitophagy is adversely affected in aged skeletal muscle, and this is thought to contribute toward the age-related decline of muscle health. While our knowledge of the molecular mechanisms that regulate mitophagy are derived mostly from work in non-muscle cells, whether these mechanisms are conferred in muscle under physiological conditions has not been thoroughly investigated. Recent findings from our laboratory and those of others have made several novel contributions to this field. Herein, we consolidate current literature, including our recent work, while evaluating how ubiquitin-dependent mitophagy is regulated both in muscle and non-muscle cells through the steps of mitochondrial fission, ubiquitylation, and autophagosomal engulfment. During ubiquitin-dependent mitophagy in non-muscle cells, mitochondrial depolarization activates PINK1-Parkin signaling to elicit mitochondrial ubiquitylation. TANK-binding kinase 1 (TBK1) then activates autophagy receptors, which in turn, tether ubiquitylated mitochondria to autophagosomes prior to lysosomal degradation. In skeletal muscle, evidence supporting the involvement of PINK1-Parkin signaling in mitophagy is lacking. Instead, 5′-AMP-activated protein kinase (AMPK) is emerging as a critical regulator. Mechanistically, AMPK activation promotes mitochondrial fission before enhancing autophagosomal engulfment of damaged mitochondria possibly via TBK1. While TBK1 may be a point of convergence between PINK1-Parkin and AMPK signaling in muscle, the critical question that remains is: whether mitochondrial ubiquitylation is required for mitophagy. In future, improving understanding of molecular processes that regulate mitophagy in muscle will help to develop novel strategies to promote healthy aging.

Aging of the Retina: Molecular and Metabolic Turbulences and Potential Interventions

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Laura Campello ◽  
Nivedita Singh ◽  
Jayshree Advani ◽  
Anupam K. Mondal ◽  
Ximena Corso-Diaz ◽  
...  
Keyword(s):  
Healthy Aging ◽  
Cell Types ◽  
Lifestyle Changes ◽  
Annual Review ◽  
Past Century ◽  
Publication Date ◽  
Vision Science ◽  
Human Lifespan ◽  
Cellular Events ◽  
Age Related

Multifaceted and divergent manifestations across tissues and cell types have curtailed advances in deciphering the cellular events that accompany advanced age and contribute to morbidities and mortalities. Increase in human lifespan during the past century has heightened awareness of the need to prevent age-associated frailty of neuronal and sensory systems to allow a healthy and productive life. In this review, we discuss molecular and physiological attributes of aging of the retina, with a goal of understanding age-related impairment of visual function. We highlight the epigenome–metabolism nexus and proteostasis as key contributors to retinal aging and discuss lifestyle changes as potential modulators of retinal function. Finally, we deliberate promising intervention strategies for promoting healthy aging of the retina for improved vision. Expected final online publication date for the Annual Review of Vision Science, Volume 7 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Recent advances in the development of legumain-selective chemical probes and peptide prodrugs

2019 ◽  
Vol 400 (12) ◽  
pp. 1529-1550 ◽  
Author(s):  
Marcin Poreba
Keyword(s):  
Small Molecule ◽  
Molecular Target ◽  
Biological Processes ◽  
Chemical Probes ◽  
Moth Bean ◽  
Historical Perspectives ◽  
Asparaginyl Endopeptidase ◽  
Cellular Events ◽  
Leguminous Seeds ◽  
Extracellular Activity

Abstract Legumain, which is also known as vacuolar processing enzyme (VPE) or asparaginyl endopeptidase (AEP), is a cysteine protease that was first discovered and characterized in the leguminous seeds of the moth bean in the early 1990s. Later, this enzyme was also detected in higher organisms, including eukaryotes. This pH-dependent protease displays the highest activity in acidic endolysosomal compartments; however, legumain also displays nuclear, cytosolic and extracellular activity when stabilized by other proteins or intramolecular complexes. Based on the results from over 25 years of research, this protease is involved in multiple cellular events, including protein degradation and antigen presentation. Moreover, when dysregulated, this protease contributes to the progression of several diseases, with cancer being the well-studied example. Research on legumain biology was undoubtedly facilitated by the use of small molecule chemical tools. Therefore, in this review, I present the historical perspectives and most current strategies for the development of small molecule substrates, inhibitors and activity-based probes for legumain. These tools are of paramount importance in elucidating the roles of legumain in multiple biological processes. Finally, as this enzyme appears to be a promising molecular target for anticancer therapies, the development of legumain-activated prodrugs is also described.

scholarly journals PDLIM5 inhibits STUB1-mediated degradation of SMAD3 and promotes the migration and invasion of lung cancer cells

2020 ◽  
Vol 295 (40) ◽  
pp. 13798-13811 ◽  
Author(s):  
Yueli Shi ◽  
Xinyu Wang ◽  
Zhiyong Xu ◽  
Ying He ◽  
Chunyi Guo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Effector Proteins ◽  
Scaffolding Protein ◽  
Migration And Invasion ◽  
Tgfβ Signaling ◽  
Mesenchymal Transition ◽  
Protein Levels ◽  
Smad3 Protein

Transforming growth factor β (TGFβ) signaling plays an important role in regulating tumor malignancy, including in non–small cell lung cancer (NSCLC). The major biological responses of TGFβ signaling are determined by the effector proteins SMAD2 and SMAD3. However, the regulators of TGFβ–SMAD signaling are not completely revealed yet. Here, we showed that the scaffolding protein PDLIM5 (PDZ and LIM domain protein 5, ENH) critically promotes TGFβ signaling by maintaining SMAD3 stability in NSCLC. First, PDLIM5 was highly expressed in NSCLC compared with that in adjacent normal tissues, and high PDLIM5 expression was associated with poor outcome. Knockdown of PDLIM5 in NSCLC cells decreased migration and invasion in vitro and lung metastasis in vivo. In addition, TGFβ signaling and TGFβ-induced epithelial–mesenchymal transition was repressed by PDLIM5 knockdown. Mechanistically, PDLIM5 knockdown resulted in a reduction of SMAD3 protein levels. Overexpression of SMAD3 reversed the TGFβ-signaling-repressing and anti-migration effects induced by PDLIM5 knockdown. Notably, PDLIM5 interacted with SMAD3 but not SMAD2 and competitively suppressed the interaction between SMAD3 and its E3 ubiquitin ligase STUB1. Therefore, PDLIM5 protected SMAD3 from STUB1-mediated proteasome degradation. STUB1 knockdown restored SMAD3 protein levels, cell migration, and invasion in PDLIM5-knockdown cells. Collectively, our findings indicate that PDLIM5 is a novel regulator of basal SMAD3 stability, with implications for controlling TGFβ signaling and NSCLC progression.

scholarly journals Unifying Themes in Microbial Associations with Animal and Plant Hosts Described Using the Gene Ontology

2010 ◽  
Vol 74 (4) ◽  
pp. 479-503 ◽  
Author(s):  
Trudy Torto-Alalibo ◽  
Candace W. Collmer ◽  
Michelle Gwinn-Giglio ◽  
Magdalen Lindeberg ◽  
Shaowu Meng ◽  
...  
Keyword(s):  
Gene Ontology ◽  
Effector Proteins ◽  
Biological Processes ◽  
Gene Products ◽  
Host Defenses ◽  
Host Interactions ◽  
Microbial Associations ◽  
Bioinformatic Approaches ◽  
Go Terms ◽  
Diverse Plant

SUMMARY Microbes form intimate relationships with hosts (symbioses) that range from mutualism to parasitism. Common microbial mechanisms involved in a successful host association include adhesion, entry of the microbe or its effector proteins into the host cell, mitigation of host defenses, and nutrient acquisition. Genes associated with these microbial mechanisms are known for a broad range of symbioses, revealing both divergent and convergent strategies. Effective comparisons among these symbioses, however, are hampered by inconsistent descriptive terms in the literature for functionally similar genes. Bioinformatic approaches that use homology-based tools are limited to identifying functionally similar genes based on similarities in their sequences. An effective solution to these limitations is provided by the Gene Ontology (GO), which provides a standardized language to describe gene products from all organisms. The GO comprises three ontologies that enable one to describe the molecular function(s) of gene products, the biological processes to which they contribute, and their cellular locations. Beginning in 2004, the Plant-Associated Microbe Gene Ontology (PAMGO) interest group collaborated with the GO consortium to extend the GO to accommodate terms for describing gene products associated with microbe-host interactions. Currently, over 900 terms that describe biological processes common to diverse plant- and animal-associated microbes are incorporated into the GO database. Here we review some unifying themes common to diverse host-microbe associations and illustrate how the new GO terms facilitate a standardized description of the gene products involved. We also highlight areas where new terms need to be developed, an ongoing process that should involve the whole community.

scholarly journals Roles of Rack1 Proteins in Fungal Pathogenesis

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Xue Zhang ◽  
Rashmi Jain ◽  
Guotian Li
Keyword(s):  
Fungal Pathogens ◽  
Recent Progress ◽  
Pathogenic Fungi ◽  
Life Cycles ◽  
Scaffolding Protein ◽  
Fungal Pathogenesis ◽  
Biological Processes ◽  
Infection Processes

Pathogenic fungi cause diseases on various organisms. Despite their differences in life cycles, fungal pathogens use well-conserved proteins and pathways to regulate developmental and infection processes. In this review, we focus on Rack1, a multifaceted scaffolding protein involved in various biological processes. Rack1 is well conserved in eukaryotes and plays important roles in fungi, though limited studies have been conducted. To accelerate the study of Rack1 proteins in fungi, we review the functions of Rack1 proteins in model and pathogenic fungi and summarize recent progress on how Rack1 proteins are involved in fungal pathogenesis.

scholarly journals The serine/threonine kinase Par1b regulates epithelial lumen polarity via IRSp53-mediated cell–ECM signaling

2011 ◽  
Vol 192 (3) ◽  
pp. 525-540 ◽  
Author(s):  
David Cohen ◽  
Dawn Fernandez ◽  
Francisco Lázaro-Diéguez ◽  
Anne Müsch
Keyword(s):  
Mdck Cells ◽  
Adherens Junction ◽  
Cell Spreading ◽  
Effector Proteins ◽  
Fiber Formation ◽  
Scaffolding Protein ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Domain 3 ◽  
Guanosine Triphosphatase

The serine/threonine kinase Par1b promotes cell–cell adhesion and determines the polarity of the luminal domain in epithelial cells. In this study, we demonstrate that Par1b also regulates cell–extracellular matrix (ECM) signaling in kidney-derived Madin–Darby canine kidney (MDCK) cells and identified the rho–guanosine triphosphatase adaptor and scaffolding protein IRSp53 as a Par1b substrate involved in this pathway. Par1b overexpression inhibits basal lamina formation, cell spreading, focal adhesion, stress fiber formation, and compaction, whereas Par1b depletion has the opposite effect. IRSp53 depletion mimics Par1b overexpression on cell–ECM signaling and lumen polarity but had no effect on adherens junction formation. Par1b directly phosphorylates IRSp53 on S366 in cell lysates and stimulates phosphorylation on S453/3/5 via an indirect mechanism. A Par1b phosphorylation–deficient IRSp53 mutant but not the wild-type protein efficiently rescues both the cell spreading and the lumen polarity defects in Par1b MDCK cells. Our data suggest a model in which Par1b phosphorylation prevents recruitment of IRSp53 effector proteins to its Src homology domain 3 by promoting 14-3-3 binding in the vicinity of that domain.

scholarly journals Regeneration is a partial redeployment of the embryonic gene network

2019 ◽  
Author(s):  
Jacob F. Warner ◽  
Aldine R. Amiel ◽  
Hereroa Johnston ◽  
Eric Röttinger
Keyword(s):  
Embryonic Development ◽  
Gene Network ◽  
Regulatory Networks ◽  
Developmental Trajectories ◽  
Regenerative Process ◽  
Whole Body ◽  
Biological Processes ◽  
Cellular Functions ◽  
Cellular Events ◽  
Transcriptomic Level

AbstractFor more than a century, researchers have been trying to understand the relationship between embryogenesis and regeneration (Morgan 1901). A long-standing hypothesis is that biological processes originally used during embryogenesis are re-deployed during regeneration. In the past decade, we have begun to understand the relationships of genes and their organization into regulatory networks responsible for driving embryogenesis (Davidson et al. 2002; Röttinger et al. 2012) and regeneration (Srivastava et al. 2014; Lobo and Levin 2015; Rodius et al. 2016) in diverse taxa. Here, we compare these networks in the same species to investigate how regeneration re-uses genetic interactions originally set aside for embryonic development. Using a uniquely suited embryonic development and whole-body regeneration model, the sea anemone Nematostella vectensis, we show that at the transcriptomic level the regenerative program partially re-uses elements of the embryonic gene network in addition to a small cohort of genes that are only activated during regeneration. We further identified co-expression modules that are either i) highly conserved between these two developmental trajectories and involved in core biological processes or ii) regeneration specific modules that drive cellular events unique to regeneration. Finally, our functional validation reveals that apoptosis is a regeneration-specific process in Nematostella and is required for the initiation of the regeneration program. These results indicate that regeneration reactivates embryonic gene modules to accomplish basic cellular functions but deploys a novel gene network logic to activate the regenerative process.

scholarly journals Genetic variation in ALDH4A1 predicts muscle health over the lifespan and across species

2021 ◽  
Author(s):  
Osvaldo Villa ◽  
Nicole L. Stuhr ◽  
Chia-An Yen ◽  
Eileen M. Crimmins ◽  
Thalida Em Arpawong ◽  
...  
Keyword(s):  
Stress Responses ◽  
Predictive Biomarker ◽  
Loss Of Function ◽  
C Elegans ◽  
Muscle Aging ◽  
Age Related ◽  
The Us ◽  
Muscle Health ◽  
Human Participants ◽  
Long Term Impact

Environmental stress can negatively impact organismal aging, however, the long-term impact of endogenously derived reactive oxygen species from normal cellular metabolism remains less clear. Here we define the evolutionarily conserved mitochondrial enzyme ALH-6/ALDH4A1 as a biomarker for age-related changes in muscle health by combining C. elegans genetics and a gene-wide association study (GeneWAS) from aged human participants of the US Health and Retirement Study (HRS)1–4. In a screen for mutations that activate SKN-1-dependent oxidative stress responses in the muscle of C. elegans5–7, we identified 96 independent genetic mutants harboring loss-of-function alleles of alh-6, exclusively. These genetic mutations map across the ALH-6 polypeptide, which lead to age-dependent loss of muscle health. Intriguingly, genetic variants in ALDH4A1 differentially impact age-related muscle function in humans. Taken together, our work uncovers mitochondrial alh-6/ALDH4A1 as a critical component of normal muscle aging across species and a predictive biomarker for muscle health over the lifespan.

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