Endocytosis and human innate immunity

Xiang, Shuanglin

doi:10.29245/2578-3009/2018/1.1121

Cited by 14 publications

(3 citation statements)

References 45 publications

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“…Like other RIN family members, RIN3 has guanine nucleotide exchange factory (GEF) activity for RAB5 GTPases 53 , which are required for early endosome and phagosome biogenesis and function 54 . Interestingly, RABEP1 (Rab-GTPase binding effector protein 1) also encodes a RAB5 effector protein that is required for early endosome membrane fusion and trafficking 55,56 . Two other novel candidate AD risk genes that we nominated in this study, AP4E1 and AP4M1 , encode two of the four subunits of the heterotetrameric adaptor protein complex 4 (AP-4) , which is required for the sorting of transmembrane proteins like APP from the trans-Golgi network (TGN) to endosomes 57,58 .…”

Section: Discussionmentioning

confidence: 99%

Integration of Alzheimer’s disease genetics and myeloid genomics reveals novel disease risk mechanisms

Novikova

Kapoor

Tcw

et al. 2019

Preprint

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Genome-wide association studies (GWAS) have identified more than thirty loci associated with Alzheimer's disease (AD), but the causal variants, regulatory elements, genes and pathways remain largely unknown thus impeding a mechanistic understanding of AD pathogenesis. Previously, we showed that AD risk alleles are enriched in myeloid-specific epigenomic annotations. Here, we show that they are specifically enriched in active enhancers of monocytes, macrophages and microglia. We integrated AD GWAS signals with myeloid epigenomic and transcriptomic datasets using novel analytical approaches to link myeloid enhancer activity to target gene expression regulation and AD risk modification. We nominate candidate AD risk enhancers and identify their target causal genes (including AP4E1, AP4M1 , APBB3 , BIN1 , CD2AP , MS4A4A , MS4A6A , PILRA , RABEP1 , SPI1 , SPPL2A , TP53INP1 , ZKSCAN1 , and ZYX ) in sixteen loci. Fine-mapping of these enhancers nominates candidate functional variants that likely modify disease susceptibility by regulating causal gene expression in myeloid cells. In the MS4A locus we identified a single candidate functional variant and validated it experimentally in human induced pluripotent stem cell (hiPSC)-derived microglia. Combined, these results strongly implicate dysfunction of the myeloid endolysosomal system in the etiology of AD. causal gene expression in eight loci, and experimentally validated one of these candidate causal variants in the MS4A locus in human induced pluripotent stem cell (hiPSC)-derived microglia. Results AD risk alleles are specifically enriched in active enhancers of monocytes, macrophages and microgliaOur earlier analyses showed a significant enrichment of AD risk alleles in various myeloid-specific epigenomic annotations, but not in brain or other tissues 15 . To further dissect this enrichment, we used ChIP-Seq profiles of histone modifications that define the chromatin signatures of regulatory elements (H3K27ac for active enhancers and promoters, H3K4me1 for enhancers, and H3K4me2 for active enhancers and promoters) from monocytes, macrophages and microglia to annotate the genome with myeloid active enhancers (AE), active promoters (AP), primed enhancers (PE) and primed promoters (PP) (see Methods) [18][19][20] . To identify which of these myeloid regulatory elements are enriched for AD risk alleles, we performed stratified LD score regression (LDSC) 21 of AD single nucleotide polymorphism (SNP) heritability partitioned by the aforementioned epigenomic annotations using the International Genomics of Alzheimer's Project (IGAP) AD GWAS dataset 22 . This analysis revealed selective enrichment of AD risk alleles in active enhancers of monocytes, macrophages and microglia (Figure 1a). In contrast, schizophrenia SNP heritability (using the Psychiatric Genomics Consortium SCZ GWAS dataset as control 23 ) was not enriched in any of these myeloid regulatory elements (Figure 1a). To identify TFs that likely regulate the activity of myeloid enhancers, we performed de novo motif an...

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Section: Discussionmentioning

confidence: 99%

Integration of Alzheimer’s disease genetics and myeloid genomics reveals novel disease risk mechanisms

Novikova

Kapoor

Tcw

et al. 2019

Preprint

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“…The cellular uptake of EVs varies according to cell type. EVs generated in the presence of jakinibs, especially lymphoid and monocytic origin, are more easily internalized by neutrophils and monocytes due to the specific receptors expressed by these phagocytic cells [ 64 , 65 ]. The high phagocytic activity of neutrophils and monocytes, and their role in clearing material released by dying cells, contributes to their ability to take up EVs efficiently [ 66 ].…”

Section: Discussionmentioning

confidence: 99%

Janus kinase inhibitors modify the fatty acid profile of extracellular vesicles and modulate the immune response

Daza Zapata,

Álvarez,

Vásquez Duque

et al. 2024

Heliyon

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“…Interestingly, the protein–RNA recognition method described here identified a compatible sequence in the S1A-domain for the post-transcriptional promotion of PIKFYVE and post-transcriptional repression of RABEP1 ( Figure 2 ). PIKFYVE (phosphoinositide kinase FYVE-type) synthesizes phosphatidyl-inositol-3,5-bisphosphate (PI(3,5)P2; Ou et al, 2020 ) and RABEP1 (RAB GTPase binding effector protein 1) functions as a vital activator and molecular switch for RAB5, an early endosome associated GTPase ( Ding and Xiang, 2018 ), which positively regulates PI(3)P synthesis ( Di Paolo and De Camilli, 2006 ). PI(3)P is a major determinant of early endosome membrane identity, while PI(3,5)P2 is a major determinant of late endosome membrane identity ( Di Paolo and De Camilli, 2006 ), ( Figure 4 ).…”

Section: Discussionmentioning

confidence: 99%

Theoretical Analysis of S, M and N Structural Proteins by the Protein–RNA Recognition Code Leads to Genes/proteins that Are Relevant to the SARS-CoV-2 Life Cycle and Pathogenesis

Nahálka

2021

Front. Genet.

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In this conceptual review, based on the protein–RNA recognition code, some theoretical sequences were detected in the spike (S), membrane (M) and capsid (N) proteins that may post-transcriptionally regulate the host genes/proteins in immune homeostasis, pulmonary epithelial tissue homeostasis, and lipid homeostasis. According to the review of literature, the spectrum of identified genes/proteins shows that the virus promotes IL1α/β–IL1R1 signaling (type 1 immunity) and immunity defense against helminths and venoms (type 2 immunity). In the alteration of homeostasis in the pulmonary epithelial tissue, the virus blocks the function of cilia and the molecular programs that are involved in wound healing (EMT and MET). Additionally, the protein–RNA recognition method described here identifies compatible sequences in the S1A-domain for the post-transcriptional promotion of PIKFYVE, which is one of the critical factors for SARS-CoV-2 entry to the host cell, and for the post-transcriptional repression of xylulokinase XYLB. A decrease in XYLB product (Xu5P) in plasma was proposed as one of the potential metabolomics biomarkers of COVID-19. In summary, the protein–RNA recognition code leads to protein genes relevant to the SARS-CoV-2 life cycle and pathogenesis.

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Endocytosis and human innate immunity

Cited by 14 publications

References 45 publications

Integration of Alzheimer’s disease genetics and myeloid genomics reveals novel disease risk mechanisms

Integration of Alzheimer’s disease genetics and myeloid genomics reveals novel disease risk mechanisms

Janus kinase inhibitors modify the fatty acid profile of extracellular vesicles and modulate the immune response

Theoretical Analysis of S, M and N Structural Proteins by the Protein–RNA Recognition Code Leads to Genes/proteins that Are Relevant to the SARS-CoV-2 Life Cycle and Pathogenesis

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