AHNAK: The quiet giant in calcium homeostasis

Sundararaj, Srinivasan; Ravindran, Agin

doi:10.1016/j.ceca.2021.102403

Cited by 20 publications

(22 citation statements)

References 54 publications

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“…AHNAK is a large protein orchestrating a range of diverse biological processes and chemotherapeutic responses [ 25 ]. Several studies have shown that the dysregulated levels of AHNAK are linked with numerous cancers, such as breast cancer, gastric cancer, and ovarian cancer [ 7 , 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

The AHNAK induces increased IL-6 production in CD4+ T cells and serves as a potential diagnostic biomarker for recurrent pregnancy loss

Liu

Feng

et al. 2022

Clinical and Experimental Immunology

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Disorganized maternal–fetal immune tolerance contributes to the occurrence of unexplained recurrent pregnancy loss (RPL). AHNAK is a scaffolding protein participating in the regulation of Ca2+ entry into T cells and the pathophysiology of diverse diseases. We performed differential gene expression analysis in decidual immune cells (DICs) isolated from three patients with RPL and from three healthy controls via RNA-sequencing (RNA-seq), which revealed 407 differentially expressed genes (DEGs). Among these DEGs, we underscored the clinical significance of elevated AHNAK mRNA and protein levels in DICs, peripheral blood mononuclear cells (PBMCs), and decidua of the patients with RPL, suggesting its potential use as a biomarker for the diagnosis of RPL. Especially, the ratios of decidual and blood AHNAK+CD4+ T cells in the CD4+ T cell population were significantly increased in patients with RPL, and the loss of AHNAK was further shown to inhibit interleukin (IL)-6 secretion in the CD4+ Jurkat cell line. Similar patterns were also observed in the clinical decidual and blood specimens. We uncovered that the AHNAK+CD4+ T cells could secrete more IL-6 than that the corresponding AHNAK-CD4+ T cells. Moreover, the frequencies of decidual and blood IL-6+CD4+ T cells in the CD4+ T-cell population were also increased in patients with RPL and showed significant positive correlations with the frequencies of AHNAK+CD4+ T cells. Our findings suggest that the elevated AHNAK expressed by CD4+ T cells may be involved in the immune dysregulation of RPL by increasing IL-6 production, illustrating its potential as a novel intervention target for RPL.

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Section: Discussionmentioning

confidence: 99%

The AHNAK induces increased IL-6 production in CD4+ T cells and serves as a potential diagnostic biomarker for recurrent pregnancy loss

Liu

Feng

et al. 2022

Clinical and Experimental Immunology

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“…As a third example of an activity-induced homeostatic protein, synthesis of AHNAK, a large scaffolding protein, is significantly increased. AHNAK interacts with voltage-sensitive L-type Ca 2+ channels in the plasma membrane and has been shown to play an essential role in calcium homeostasis ( Sundararaj et al, 2021 ), suggesting that increased AHNAK may have homeostatic functions following PTZ-induced neuronal depolarization.…”

Section: Discussionmentioning

confidence: 99%

Activity-Induced Cortical Glutamatergic Neuron Nascent Proteins

et al. 2022

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Neuronal activity initiates signaling cascades that culminate in diverse outcomes including structural and functional neuronal plasticity, and metabolic changes. While studies have revealed activity-dependent neuronal cell type-specific transcriptional changes, unbiased quantitative analysis of cell-specific activity-induced dynamics in newly synthesized proteins (NSPs) synthesis in vivo has been complicated by cellular heterogeneity and a relatively low abundance of NSPs within the proteome in the brain. Here we combined targeted expression of mutant MetRS (methionine tRNA synthetase) in genetically defined cortical glutamatergic neurons with tight temporal control of treatment with the noncanonical amino acid, azidonorleucine, to biotinylate NSPs within a short period after pharmacologically induced seizure in male and female mice. By purifying peptides tagged with heavy or light biotin-alkynes and using direct tandem mass spectrometry detection of biotinylated peptides, we quantified activity-induced changes in cortical glutamatergic neuron NSPs. Seizure triggered significant changes in ∼300 NSPs, 33% of which were decreased by seizure. Proteins mediating excitatory and inhibitory synaptic plasticity, including SynGAP1, Pak3, GEPH1, Copine-6, and collybistin, and DNA and chromatin remodeling proteins, including Rad21, Smarca2, and Ddb1, are differentially synthesized in response to activity. Proteins likely to play homeostatic roles in response to activity, such as regulators of proteastasis, intracellular ion control, and cytoskeleton remodeling proteins, are activity induced. Conversely, seizure decreased newly synthetized NCAM, among others, suggesting that seizure induced degradation. Overall, we identified quantitative changes in the activity-induced nascent proteome from genetically defined cortical glutamatergic neurons as a strategy to discover downstream mediators of neuronal plasticity and generate hypotheses regarding their function. SIGNIFICANCE STATEMENT Activity-induced neuronal and synaptic plasticity are mediated by changes in the protein landscape, including changes in the activity-induced newly synthesized proteins; however, identifying neuronal cell type-specific nascent proteome dynamics in the intact brain has been technically challenging. We conducted an unbiased proteomic screen from which we identified significant activity-induced changes in ∼300 newly synthesized proteins in genetically defined cortical glutamatergic neurons within 20 h after pharmacologically induced seizure. Bioinformatic analysis of the dynamic nascent proteome indicates that the newly synthesized proteins play diverse roles in excitatory and inhibitory synaptic plasticity, chromatin remodeling, homeostatic mechanisms, and proteasomal and metabolic functions, extending our understanding of the diversity of plasticity mechanisms.

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“…The expression of CX3CR1 may be associated with the pathological mechanism of severe COVID-19, and the low expression of CX3CR1 in immune cells may contribute to the antiviral response [ 42 ]. As a scaffolding protein in many protein-protein interactions, ANHAK can coordinate a variety of biological processes, including tumor suppression and immune regulation [ 43 ]. ANHAK is the pro-viral factor for SARS-CoV-2 infection [ 44 ], while it is associated with COVID-19 in the progression of chronic obstructive pulmonary disease (COPD) [ 45 ].…”

Section: Resultsmentioning

confidence: 99%

Identification of COVID-19-Associated DNA Methylation Variations by Integrating Methylation Array and scRNA-Seq Data at Cell-Type Resolution

Wang

Xiong

Yang

et al. 2022

Genes

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Single-cell transcriptome studies have revealed immune dysfunction in COVID-19 patients, including lymphopenia, T cell exhaustion, and increased levels of pro-inflammatory cytokines, while DNA methylation plays an important role in the regulation of immune response and inflammatory response. The specific cell types of immune responses regulated by DNA methylation in COVID-19 patients will be better understood by exploring the COVID-19 DNA methylation variation at the cell-type level. Here, we developed an analytical pipeline to explore single-cell DNA methylation variations in COVID-19 patients by transferring bulk-tissue-level knowledge to the single-cell level. We discovered that the methylation variations in the whole blood of COVID-19 patients showed significant cell-type specificity with remarkable enrichment in gamma-delta T cells and presented a phenomenon of hypermethylation and low expression. Furthermore, we identified five genes whose methylation variations were associated with several cell types. Among them, S100A9, AHNAK, and CX3CR1 have been reported as potential COVID-19 biomarkers previously, and the others (TRAF3IP3 and LFNG) are closely associated with the immune and virus-related signaling pathways. We propose that they might serve as potential epigenetic biomarkers for COVID-19 and could play roles in important biological processes such as the immune response and antiviral activity.

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AHNAK: The quiet giant in calcium homeostasis

Cited by 20 publications

References 54 publications

The AHNAK induces increased IL-6 production in CD4+ T cells and serves as a potential diagnostic biomarker for recurrent pregnancy loss

The AHNAK induces increased IL-6 production in CD4+ T cells and serves as a potential diagnostic biomarker for recurrent pregnancy loss

Activity-Induced Cortical Glutamatergic Neuron Nascent Proteins

Identification of COVID-19-Associated DNA Methylation Variations by Integrating Methylation Array and scRNA-Seq Data at Cell-Type Resolution

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