RESUMO
Atr is a serine/threonine kinase, known to sense single-stranded DNA breaks and activate the DNA damage checkpoint by phosphorylating Chek1, which inhibits Cdc25, causing cell cycle arrest. This pathway has not been implicated in neuroregeneration. We show that in Drosophila sensory neurons removing Atr or Chek1, or overexpressing Cdc25 promotes regeneration, whereas Atr or Chek1 overexpression, or Cdc25 knockdown impedes regeneration. Inhibiting the Atr-associated checkpoint complex in neurons promotes regeneration and improves synapse/behavioral recovery after CNS injury. Independent of DNA damage, Atr responds to the mechanical stimulus elicited during regeneration, via the mechanosensitive ion channel Piezo and its downstream NO signaling. Sensory neuron-specific knockout of Atr in adult mice, or pharmacological inhibition of Atr-Chek1 in mammalian neurons in vitro and in flies in vivo enhances regeneration. Our findings reveal the Piezo-Atr-Chek1-Cdc25 axis as an evolutionarily conserved inhibitory mechanism for regeneration, and identify potential therapeutic targets for treating nervous system trauma.
Assuntos
Axônios/metabolismo , Quinase 1 do Ponto de Checagem/genética , Canais Iônicos/genética , Regeneração Nervosa/genética , Animais , Animais Geneticamente Modificados , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Quinase 1 do Ponto de Checagem/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Células HEK293 , Humanos , Canais Iônicos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/genéticaRESUMO
A recent outbreak of coronavirus disease 2019 (COVID-19) caused by the single-stranded enveloped RNA virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has developed into a global pandemic, after it was first reported in Wuhan in December 2019. SARS-CoV-2 is an emerging virus, and little is known about the basic characteristics of this pathogen, the underlying mechanism of infection, and the potential treatments. The immune system has been known to be actively involved in viral infections. To facilitate the development of COVID-19 treatments, the understanding of immune regulation by this viral infection is urgently needed. This review describes the mechanisms of immune system involvement in viral infections and provides an overview of the dysregulation of immune responses in COVID-19 patients in recent studies. Furthermore, we emphasize the role of gut microbiota in regulating immunity and summarized the impact of SARS-CoV-2 infection on the composition of the microbiome. Overall, this review provides insights for understanding and developing preventive and therapeutic strategies by regulating the immune system and microbiota.
