14-3-3 isoforms bind directly exon B of the 5′-UTR of human surfactant protein A2 mRNA

Noutsios, Georgios T.; Ghattas, Paul; Bennett, Stephanie; Floros, Joanna

doi:10.1152/ajplung.00088.2015

Cited by 13 publications

(13 citation statements)

References 70 publications

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“…6 ). Though the host miRNAs cannot target the YWHAZ pro-survival protein 76 , they can induce expression surfactant protein A2 77 , which might be indirectly modulated through viral protein NSP7 (Fig. 6 ).…”

Section: Discussionmentioning

confidence: 99%

Lung transcriptome of a COVID-19 patient and systems biology predictions suggest impaired surfactant production which may be druggable by surfactant therapy

Islam

Khan

2020

Sci Rep

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An incomplete understanding of the molecular mechanisms behind impairment of lung pathobiology by COVID-19 complicates its clinical management. In this study, we analyzed the gene expression pattern of cells obtained from biopsies of COVID-19-affected patient and compared to the effects observed in typical SARS-CoV-2 and SARS-CoV-infected cell-lines. We then compared gene expression patterns of COVID-19-affected lung tissues and SARS-CoV-2-infected cell-lines and mapped those to known lung-related molecular networks, including hypoxia induced responses, lung development, respiratory processes, cholesterol biosynthesis and surfactant metabolism; all of which are suspected to be downregulated following SARS-CoV-2 infection based on the observed symptomatic impairments. Network analyses suggest that SARS-CoV-2 infection might lead to acute lung injury in COVID-19 by affecting surfactant proteins and their regulators SPD, SPC, and TTF1 through NSP5 and NSP12; thrombosis regulators PLAT, and EGR1 by ORF8 and NSP12; and mitochondrial NDUFA10, NDUFAF5, and SAMM50 through NSP12. Furthermore, hypoxia response through HIF-1 signaling might also be targeted by SARS-CoV-2 proteins. Drug enrichment analysis of dysregulated genes has allowed us to propose novel therapies, including lung surfactants, respiratory stimulants, sargramostim, and oseltamivir. Our study presents a distinct mechanism of probable virus induced lung damage apart from cytokine storm.

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Section: Discussionmentioning

confidence: 99%

Lung transcriptome of a COVID-19 patient and systems biology predictions suggest impaired surfactant production which may be druggable by surfactant therapy

Islam

Khan

2020

Sci Rep

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“…Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein beta (YWHAB) was downregulated in the white pulp of spleen, heart and renal cortex of COVID-19 patients (SI Figure 8). It is a member of the 14-3-3 protein family, which mediates signal transduction by binding to phosphoserine protein and participates in metabolism, apoptosis and cell cycle regulation 191 .…”

Section: Stage 3: Proliferationmentioning

confidence: 99%

Multi-organ Proteomic Landscape of COVID-19 Autopsies

Nie¹,

Qian²,

Sun³

et al. 2020

Preprint

149

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The molecular pathology of multi-organ injuries in COVID-19 patients remains unclear, preventing effective therapeutics development. Here, we report an in-depth multi-organ proteomic landscape of COVID-19 patient autopsy samples. By integrative analysis of proteomes of seven organs, namely lung, spleen, liver, heart, kidney, thyroid and testis, we characterized 11,394 proteins, in which 5336 were perturbed in COVID-19 patients compared to controls. Our data showed that CTSL, rather than ACE2, was significantly upregulated in the lung from COVID-19 patients. Dysregulation of protein translation, glucose metabolism, fatty acid metabolism was detected in multiple organs. Our data suggested upon SARS-CoV-2 infection, hyperinflammation might be triggered which in turn induces damage of gas exchange barrier in the lung, leading to hypoxia, angiogenesis, coagulation and fibrosis in the lung, kidney, spleen, liver, heart and thyroid. Evidence for testicular injuries included reduced Leydig cells, suppressed cholesterol biosynthesis and sperm mobility. In summary, this study depicts the multi-organ proteomic landscape of COVID-19 autopsies, and uncovered dysregulated proteins and biological processes, offering novel therapeutic clues.

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“…Several studies have identified differences between SP-A1 and SP-A2 in both qualitative (i.e., functional, biochemical, and/or structural) (45)(46)(47)(48), and quantitative (regulatory) functions (46,(49)(50)(51)(52)(53)(54)(55). In particular, these include surfactant secretion modulation (46), cytokine production (56)(57)(58), and phagocytosis by AM (47,48,59).…”

Section: Introductionmentioning

confidence: 99%

Sex-Specific Regulation of Gene Expression Networks by Surfactant Protein A (SP-A) Variants in Alveolar Macrophages in Response to Klebsiella pneumoniae

et al. 2020

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Surfactant protein A (SP-A) in addition to its surfactant-related functions interacts with alveolar macrophages (AM), the guardian cells of innate immunity in the lungs, and regulates many of its functions under basal condition and in response to various pressures, such as infection and oxidative stress. The human SPA locus consists of two functional genes, SFTPA1 and SFTPA2, and one pseudogene. The functional genes encode human SP-A1 and SP-A2 proteins, respectively, and each has been identified with several genetic variants. SPA variants differ in their ability to regulate lung function mechanics and survival in response to bacterial infection. Here, we investigated the effect of hSP-A variants on the AM gene expression profile in response to Klebsiella pneumoniae infection. We used four humanized transgenic (hTG) mice that each carried SP-A1 (6A 2 , 6A 4) or SP-A2 (1A 0 , 1A 3), and KO. AM gene expression profiling was performed after 6 h post-infection. We found: (a) significant sex differences in the expression of AM genes; (b) in response to infection, 858 (KO), 196 (6A 2), 494 (6A 4), 276 (1A 0), and 397 (1A 3) genes were identified (P < 0.05) and some of these were differentially expressed with ≥2 fold, specific to either males or females; (c) significant SP-A1 and SP-A2 variant-specific differences in AM gene expression; (d) via Ingenuity Pathway Analysis (IPA), key pathways and molecules were identified that had direct interaction with TP53, TNF, and cell cycle signaling nodes; (e) of the three pathways (TNF, TP-53, and cell cycle signaling nodes) studied here, all variants except SP-A2 (1A 3) female, showed significance for at least 2 of these pathways, and KO male showed significance for all three pathways; (f) validation of key molecules exhibited variant-specific significant differences in the expression between sexes and a similarity in gene expression profile was observed between KO and SP-A1. These results reveal for the first time a Thorenoor et al. AM Gene Regulation by SPA Variants large number of biologically relevant functional pathways influenced in a sex-specific manner by SPA variants in response to infection. These data may assist in studying molecular mechanisms of SPA mediated AM gene regulation and potentially identify novel therapeutic targets for K. pneumoniae infection.

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14-3-3 isoforms bind directly exon B of the 5′-UTR of human surfactant protein A2 mRNA

Cited by 13 publications

References 70 publications

Lung transcriptome of a COVID-19 patient and systems biology predictions suggest impaired surfactant production which may be druggable by surfactant therapy

Lung transcriptome of a COVID-19 patient and systems biology predictions suggest impaired surfactant production which may be druggable by surfactant therapy

Multi-organ Proteomic Landscape of COVID-19 Autopsies

Sex-Specific Regulation of Gene Expression Networks by Surfactant Protein A (SP-A) Variants in Alveolar Macrophages in Response to Klebsiella pneumoniae

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