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1.
Adv Immunol ; 161: 53-83, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38763702

RESUMO

Our innate immune system uses pattern recognition receptors (PRRs) as a first line of defense to detect microbial ligands and initiate an immune response. Viral nucleic acids are key ligands for the activation of many PRRs and the induction of downstream inflammatory and antiviral effects. Initially it was thought that endogenous (self) nucleic acids rarely activated these PRRs, however emerging evidence indicates that endogenous nucleic acids are able to activate host PRRs in homeostasis and disease. In fact, many regulatory mechanisms are in place to finely control and regulate sensing of self-nucleic acids by PRRs. Sensing of self-nucleic acids is particularly important in the brain, as perturbations to nucleic acid sensing commonly leads to neuropathology. This review will highlight the role of nucleic acid sensors in the brain, both in disease and homeostasis. We also indicate the source of endogenous stimulatory nucleic acids where known and summarize future directions for the study of this growing field.


Assuntos
Encéfalo , Imunidade Inata , Ácidos Nucleicos , Receptores de Reconhecimento de Padrão , Humanos , Encéfalo/metabolismo , Encéfalo/imunologia , Animais , Receptores de Reconhecimento de Padrão/metabolismo , Ácidos Nucleicos/imunologia , Ácidos Nucleicos/metabolismo , Homeostase , Transdução de Sinais
2.
Mol Cell ; 83(21): 3760-3762, 2023 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-37922869

RESUMO

In this issue, Hu and Heraud-Farlow et al.1 demonstrate that ADAR1 dsRNA editing and dsRNA binding activities are critical to repress MDA5 and PKR, respectively, and that PKR and MDA5 act in concert to induce fatality in ADAR1 KO mice.


Assuntos
Adenosina Desaminase , RNA de Cadeia Dupla , Camundongos , Animais , RNA de Cadeia Dupla/genética , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo
3.
Sci Immunol ; 8(88): eadg2979, 2023 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-37862432

RESUMO

Loss of RNA homeostasis underlies numerous neurodegenerative and neuroinflammatory diseases. However, the molecular mechanisms that trigger neuroinflammation are poorly understood. Viral double-stranded RNA (dsRNA) triggers innate immune responses when sensed by host pattern recognition receptors (PRRs) present in all cell types. Here, we report that human neurons intrinsically carry exceptionally high levels of immunostimulatory dsRNAs and identify long 3'UTRs as giving rise to neuronal dsRNA structures. We found that the neuron-enriched ELAVL family of genes (ELAVL2, ELAVL3, and ELAVL4) can increase (i) 3'UTR length, (ii) dsRNA load, and (iii) activation of dsRNA-sensing PRRs such as MDA5, PKR, and TLR3. In wild-type neurons, neuronal dsRNAs signaled through PRRs to induce tonic production of the antiviral type I interferon. Depleting ELAVL2 in WT neurons led to global shortening of 3'UTR length, reduced immunostimulatory dsRNA levels, and rendered WT neurons susceptible to herpes simplex virus and Zika virus infection. Neurons deficient in ADAR1, a dsRNA-editing enzyme mutated in the neuroinflammatory disorder Aicardi-Goutières syndrome, exhibited intolerably high levels of dsRNA that triggered PRR-mediated toxic inflammation and neuronal death. Depleting ELAVL2 in ADAR1 knockout neurons led to prolonged neuron survival by reducing immunostimulatory dsRNA levels. In summary, neurons are specialized cells where PRRs constantly sense "self" dsRNAs to preemptively induce protective antiviral immunity, but maintaining RNA homeostasis is paramount to prevent pathological neuroinflammation.


Assuntos
Infecção por Zika virus , Zika virus , Humanos , Regiões 3' não Traduzidas/genética , RNA de Cadeia Dupla , Doenças Neuroinflamatórias , Inflamação , Receptores de Reconhecimento de Padrão/genética , Neurônios
4.
Mol Immunol ; 99: 182-190, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29807326

RESUMO

Recent studies have highlighted the importance of immune sensing of cytosolic DNA of both pathogen and host origin. We aimed to examine the role of DNA sensors interferon-γ-inducible protein 16 (IFI16) and cyclic GMP-AMP synthase (cGAS) in responding to cytosolic DNA. We show IFI16 and cGAS can synergistically induce IFNb transcriptional activity in response to cytoplasmic DNA. We also examined the role of polyglutamine binding protein 1 (PQBP1), a protein predominantly expressed in lymphoid and myeloid cells that has been shown to lead to type I interferon production in response to retroviral infection. We show PQBP1 associates with cGAS and IFI16 in THP-1 cells. Unexpectedly, knockout of PQBP1 in THP-1 cells causes significantly increased type I IFN production in response to transfected cytosolic nucleic acids or DNA damage, unlike what is seen in response to retroviral infection. Overexpression of PQBP1 in HEK293 T cells impairs IFI16/cGAS-induced IFNb transcriptional activity. In human cancer patients, low expression of PQBP1 is correlated with improved survival, the opposite correlation of that seen with cGAS or IFI16 expression. Our findings suggest that PQBP1 inhibits IFI16/cGAS-induced signaling in response to cytosolic DNA, in contrast to the role of this protein in response to retroviral infection.


Assuntos
Proteínas de Transporte/imunologia , Citosol/imunologia , DNA/imunologia , Imunidade Inata/imunologia , Proteínas Nucleares/imunologia , Linhagem Celular , Dano ao DNA/imunologia , Proteínas de Ligação a DNA , Células HEK293 , Humanos , Interferon Tipo I/imunologia , Interferon beta/imunologia , Linfócitos/imunologia , Células Mieloides/imunologia , Transdução de Sinais/imunologia , Células THP-1 , Transcrição Gênica/imunologia
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