Non-random pairing of CD46 isoforms with skewing towards BC2 and C2 in activated and memory/effector T cells

Hansen, Aida S.; Bundgaard, Bettina; Møller, Bjarne Kuno; Höllsberg, Per

doi:10.1038/srep35406

Cited by 15 publications

(16 citation statements)

References 24 publications

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“…Many studies have shown that CD46 expression in HCC tissue is significantly higher than in normal tissue [57–59]. Also, CD46 is known to have alternative splicing (exons 7–9) [60, 61], and we observed a mutually exclusive exon 8 in the HBV vs. HCV comparison and an alternative 5′ splice site (exon 6) in both HBV vs. Alcohol and HCV vs. Alcohol group comparisons. That is, CD46 may be a candidate molecular biomarker for HCC.…”

Section: Discussionsupporting

confidence: 50%

Differential alternative splicing regulation among hepatocellular carcinoma with different risk factors

et al. 2019

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BackgroundHepatitis B virus (HBV), hepatitis C virus (HCV), and alcohol consumption are predominant causes of hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying how differently these causes are implicated in HCC development are not fully understood. Therefore, we investigated differential alternative splicing (AS) regulation among HCC patients with these risk factors.MethodsWe conducted a genome-wide survey of AS events associated with HCCs among HBV (n = 95), HCV (n = 47), or alcohol (n = 76) using RNA-sequencing data obtained from The Cancer Genome Atlas.ResultsIn three group comparisons of HBV vs. HCV, HBV vs. alcohol, and HCV vs. alcohol for RNA seq (ΔPSI> 0.05, FDR < 0.05), 133, 93, and 29 differential AS events (143 genes) were identified, respectively. Of 143 AS genes, eight and one gene were alternatively spliced specific to HBV and HCV, respectively. Through functional analysis over the canonical pathways and gene ontologies, we identified significantly enriched pathways in 143 AS genes including immune system, mRNA splicing-major pathway, and nonsense-mediated decay, which may be important to carcinogenesis in HCC risk factors. Among eight genes with HBV-specific splicing events, HLA-A, HLA-C, and IP6K2 exhibited more differential expression of AS events (ΔPSI> 0.1). Intron retention of HLA-A was observed more frequently in HBV-associated HCC than HCV- or alcohol-associated HCC, and intron retention of HLA-C showed vice versa. Exon 3 (based on ENST00000432678) of IP6K2 was less skipped in HBV-associated in HCC compared to HCV- or alcohol-associated HCC.ConclusionAS may play an important role in regulating transcription differences implicated in HBV-, HCV-, and alcohol-related HCC development.

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Section: Discussionsupporting

confidence: 50%

Differential alternative splicing regulation among hepatocellular carcinoma with different risk factors

et al. 2019

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“…Similarly, EBV was shown to transactivate HERV-K18 before the transcription of viral genes, by docking to the human complement receptor CD21 (59). Furthermore, HHV-6B strain PL, shown to require CD46-Cyt1 for infection (60), induced the expression of HERV-K18 mRNA in PBMCs without requirement for viral transcription and replication (20). Understanding the regulation of HERV-Env expression requires the differentiation whether a given factor is a cause or a result of particular disease or physiological condition.…”

Section: Discussionmentioning

confidence: 99%

Induction of Proinflammatory Multiple Sclerosis-Associated Retrovirus Envelope Protein by Human Herpesvirus-6A and CD46 Receptor Engagement

et al. 2018

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The aberrant expression of human endogenous retrovirus (HERV) elements of the HERV-W family has been associated with different diseases, including multiple sclerosis (MS). In particular, the expression of the envelope protein (Env) from the multiple sclerosis-associated retrovirus (MSRV), a member of HERV-W family and known for its potent proinflammatory activity, is repeatedly detected in the brain lesions and blood of MS patients. Furthermore, human herpesvirus 6 (HHV-6) infection has long been suspected to play a role in the pathogenesis of MS and neuroinflammation. We show here that both HHV-6A and stimulation of its receptor, transmembrane glycoprotein CD46, induce the expression of MSRV-Env. The engagement of extracellular domains SCR3 and SCR4 of CD46-Cyt1 isoform was required for MSRV-env transactivation, limiting thus the MSRV-Env induction to the CD46 ligands binding these domains, including C3b component of complement, specific monoclonal antibodies, and both infectious and UV-inactivated HHV-6A, but neither HHV-6B nor measles virus vaccine strain. Induction of MSRV-Env required CD46 Cyt-1 singling and was abolished by the inhibitors of protein kinase C. Finally, both membrane-expressed and secreted MSRV-Env trigger TLR4 signaling, displaying thus a proinflammatory potential, characteristic for this viral protein. These data expand the specter of HHV-6A effects in the modulation of the immune response and support the hypothesis that cross-talks between exogenous and endogenous viruses may contribute to inflammatory diseases and participate in neuroinflammation. Furthermore, they reveal a new function of CD46, known as an inhibitor of complement activation and receptor for several pathogens, in transactivation of HERV env genes, which may play an important role in the pathogenesis of inflammatory diseases.

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“…CD46-mediated signals also trigger the switch from high glycolytic activity to steady-state glycolysis in CD4+ T cells during IL-10 co-production and Th1 contraction; this change from high to low glycolysis level is mediated by the CD46-CYT-2 isoform, which becomes again the predominant CD46 isoform in contracting T lymphocytes (Kolev et al, 2015). The mechanism regulating the expression/splicing of CD46 isoforms has not yet been defined however it is known that CYT-2 is expressed predominantly in memory CD4 + T cells (Hansen et al, 2016). While mice express a complement regulator that can inactivate mouse C3b and C4b, termed Crry (Ruseva et al, 2009), a fully functional murine homologue of human CD46 in terms of its T cell function has so far not been discovered.…”

Section: Complosome-mediated Regulation Of Nutrient and Oxygen Metabomentioning

confidence: 99%

Intracellular complement − the complosome − in immune cell regulation

Arbore

Kemper

Kolev

2017

Molecular Immunology

172

158

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The complement system was defined over a century ago based on its ability to "complement" the antibody-mediated and cell-mediated immune responses against pathogens. Today our understanding of this ancient part of innate immunity has changed substantially and we know now that complement plays an undisputed pivotal role in the regulation of both innate and adaptive immunity. The complement system consists of over 50 blood-circulating, cell-surface expressed and intracellular proteins. It is key in the recognition and elimination of invading pathogens, also in the removal of self-derived danger such as apoptotic cells, and it supports innate immune responses and the initiation of the general inflammatory reactions. The long prevailing classic view of complement was that of a serum-operative danger sensor and first line of defence system, however, recent experimental and clinical evidences have demonstrated that "local" tissue and surprisingly intracellular complement (the complosome) activation impacts on normal cell physiology. This review will focus on novel aspects of intracellular complement activation and its unexpected roles in basic cell processes such as metabolism. We also discuss what the existence of the complosome potentially means for how the host handles intracellular pathogens such as viruses.

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Non-random pairing of CD46 isoforms with skewing towards BC2 and C2 in activated and memory/effector T cells

Cited by 15 publications

References 24 publications

Differential alternative splicing regulation among hepatocellular carcinoma with different risk factors

Differential alternative splicing regulation among hepatocellular carcinoma with different risk factors

Induction of Proinflammatory Multiple Sclerosis-Associated Retrovirus Envelope Protein by Human Herpesvirus-6A and CD46 Receptor Engagement

Intracellular complement − the complosome − in immune cell regulation

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