Interaction of the α7-nicotinic subunit with its human-specific duplicated dupα7 isoform in mammalian cells: Relevance in human inflammatory responses

Maldifassi, María Constanza; Martín-Sánchez, Carolina; Atienza, G.; Cedillo, José Luis; Arnalich, Francisco; Bordas, Anna; Zafra, Francisco; Giménez, Cecilio; Extremera, María; Renart, Jaime; Montiel, Carmen

doi:10.1074/jbc.ra118.003443

Cited by 32 publications

(45 citation statements)

References 48 publications

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“…MGL cells differentiated from the three iPSC cell lines demonstrated similar microglial gene expression signatures and the majority of cells expressed the microglial marker TMEM119. Consistent with literature reports of an increased CHRFAM7A/CHRNA7 ratio in mononuclear cells, including macrophages [ 32 , 33 ], RT-qPCR and immunoblot confirmed CHRFAM7A and CHRNA7 expression in iPSC-derived MGL cells.…”

Section: Discussionsupporting

confidence: 90%

iPSC-Derived Microglia for Modeling Human-Specific DAMP and PAMP Responses in the Context of Alzheimer’s Disease

Ihnatovych

Birkaya

Notari

et al. 2020

IJMS

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Neuroinflammation in Alzheimer’s disease (AD) has been the focus for identifying targetable pathways for drug development. The role of amyloid beta (Aβ), a prototype of damage-associated molecular patterns (DAMPs), has been implicated in triggering an inflammatory response. As alpha7 nicotinic acetylcholine receptor (α7 nAChR) binds Aβ with high affinity, α7 nAChR may play a role in Aβ-induced neuroinflammation. The conundrum of how α7 nAChR as the mediator of the cholinergic anti-inflammatory response may trigger an inflammatory response has not been resolved. CHRFAM7A, the uniquely human fusion gene between ULK4 and CHRNA7, is a negative regulator of α7 nAChR ionotropic function. To provide the human context, isogenic induced pluripotent stem cell (iPSC) lines were developed from CHRFAM7A null and carrier individuals by genome-editing the null line using TALENs to knock-in CHRFAM7A. In iPSC-derived microglia-like cells, CHRFAM7A mitigated Aβ uptake through the α7 nAChR. Despite the lower Aβ uptake, the presence of CHRFAM7A was associated with an innate immune response that was characterized by NF-κB activation and NF-κB target transcription (TNFA, IL6, and IL1B). LPS, a prototype PAMP, induced a heightened immune response in CHRFAM7A carriers. CHRFAM7A modified the dynamics of NF-κB translocation by prolonging its nuclear presence. CHRFAM7A modified the α7 nAChR metabotropic function, resulting in a human-specific innate immune response. This iPSC model provided an opportunity to elucidate the mechanism and establish high throughput screens.

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Section: Discussionsupporting

confidence: 90%

iPSC-Derived Microglia for Modeling Human-Specific DAMP and PAMP Responses in the Context of Alzheimer’s Disease

Ihnatovych

Birkaya

Notari

et al. 2020

IJMS

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“…This observation supports our earlier hypothesis that the emergence of CHRFAM7A could have contributed changes to immunity and human resilience/sensitivity to injury, infection, and/or inflammatory responsiveness (3, 9, 30). Because the product of CHRFAM7A regulates ligand binding to α7nAChR (15–18) encoded by CHRNA7, we compared the relative expression of CHRNA7 and CHRFAM7A in human tissues (Fig. 1 D – H ).…”

Section: Resultsmentioning

confidence: 99%

“…Several recent studies have suggested that CHRFAM7A encodes a dominant-negative inhibitor of ligand binding to α7nAChR in vitro (15–18), which can also be observed at the neuromuscular junction of transgenic mice (19). As such, CHRFAM7A has been implicated in the regulation of numerous α7nAChR-dependent antiinflammatory processes as well as in mental health, cognition, and neurodegenerative disease (20).…”

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confidence: 99%

Uniquely human CHRFAM7A gene increases the hematopoietic stem cell reservoir in mice and amplifies their inflammatory response

Costantini

Chan

Cohen

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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A subset of genes in the human genome are uniquely human and not found in other species. One example is CHRFAM7A, a dominant-negative inhibitor of the antiinflammatory α7 nicotinic acetylcholine receptor (α7nAChR/CHRNA7) that is also a neurotransmitter receptor linked to cognitive function, mental health, and neurodegenerative disease. Here we show that CHRFAM7A blocks ligand binding to both mouse and human α7nAChR, and hypothesized that CHRFAM7A-transgenic mice would allow us to study its biological significance in a tractable animal model of human inflammatory disease, namely SIRS, the systemic inflammatory response syndrome that accompanies severe injury and sepsis. We found that CHRFAM7A increased the hematopoietic stem cell (HSC) reservoir in bone marrow and biased HSC differentiation to the monocyte lineage in vitro. We also observed that while the HSC reservoir was depleted in SIRS, HSCs were spared in CHRFAM7A-transgenic mice and that these mice also had increased immune cell mobilization, myeloid cell differentiation, and a shift to inflammatory monocytes from granulocytes in their inflamed lungs. Together, the findings point to a pathophysiological inflammatory consequence to the emergence of CHRFAM7A in the human genome. To this end, it is interesting to speculate that human genes like CHRFAM7A can account for discrepancies between the effectiveness of drugs like α7nAChR agonists in animal models and human clinical trials for inflammatory and neurodegenerative disease. The findings also support the hypothesis that uniquely human genes may be contributing to underrecognized human-specific differences in resiliency/susceptibility to complications of injury, infection, and inflammation, not to mention the onset of neurodegenerative disease.

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“…After injection of oocytes with α7nAChR mRNA alone or in combination with CHRFAM7A mRNA they found that α-BTX staining was decreased in cells expressing both α7nAChR and CHRFAM7A compared to α7nAChR alone and concluded that the presence of CHRFAM7A decreases the number of functional α7nAChR. More recently, studies evaluating the effect of CHRFAM7A on α7nAChR binding have demonstrated that while both CHRFAM7A and α7nAChR are expressed simultaneously, the physical interaction between the CHRFAM7A and α7nAChR subunits results in a heteropentamer that can be trapped in the endoplasmic reticulum and decreases the expression of functional α7nAChR homopentamers that can bind their ligand [18].…”

Section: Discussionmentioning

confidence: 99%

CHRFAM7A alters binding to the neuronal alpha-7 nicotinic acetylcholine receptor

Chan

Williams

Cohen

et al. 2019

Neuroscience Letters

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Introduction: CHRFAM7A is a uniquely-human gene that encodes a human-specific variant of the alpha-7 nicotinic acetylcholine receptor (α7nAchR). While the homopentameric α7nAchR consists of 5 equal subunits, previous studies demonstrated that CHRFAM7A expression disrupts the formation of α7nAchR homopentamers. Here we use a rat neuronal cell line expressing CHRFAM7A and a transgenic mouse expressing CHRFAM7A to define the alpha-bungarotoxin (α-BTX) binding in vitro and in vivo. Methods: Rat PC12 cells were stably transfected with human CHRFAM7A. α-BTX, a protein that irreversibly binds the α7nAchR, was utilized to assess the capacity for CHRFAM7A to interfere with α 7AchR subunits using immunohistochemistry and flow cytometry. To evaluate the effects of CHRFAM7A on α7nAchR at the neuromuscular junction in vivo, transgenic mice were engineered to express the uniquely human gene CHRFAM7A under the control of the EF1-α promoter. Using this model, muscle was harvested and CHRFAM7A and CHRNA7 gene expression evaluated by PCR. Binding of α-BTX to the α7nAchR in muscle was compared in sibling-matched wild-type C57 mice by immunostaining the neuromuscular junction using α-BTX and neurofilament antibodies. Results: Expression of CHRFAM7A in transfected, but not vector cells, was confirmed by PCR and by immunoblotting using an antibody we raised to a peptide sequence unique to CHRFAM7A. CHRFAM7A decreased α-BTX binding as detected by immunohistochemistry and flow cytometry. In vivo, α-BTX co-stained with neurofilament at the neuromuscular junction in wildtype mice, however, α-BTX staining was decreased at the neuromuscular junction of CHRFAM7A transgenic mice.

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Interaction of the α7-nicotinic subunit with its human-specific duplicated dupα7 isoform in mammalian cells: Relevance in human inflammatory responses

Cited by 32 publications

References 48 publications

iPSC-Derived Microglia for Modeling Human-Specific DAMP and PAMP Responses in the Context of Alzheimer’s Disease

iPSC-Derived Microglia for Modeling Human-Specific DAMP and PAMP Responses in the Context of Alzheimer’s Disease

Uniquely human CHRFAM7A gene increases the hematopoietic stem cell reservoir in mice and amplifies their inflammatory response

CHRFAM7A alters binding to the neuronal alpha-7 nicotinic acetylcholine receptor

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