Circular RNA circZbtb20 maintains ILC3 homeostasis and function via Alkbh5-dependent m6A demethylation of Nr4a1 mRNA

Group 3 innate lymphoid cells(ILC3s)play critical roles in innate immunity and gut homeostasis.However,how ILC3 homeostasis is regulated remains elusive.Here,we identified a novel circular RNA,circZbtb20,that is highly expressed in ILC3s and required for their maintenance and function.CircZbtb20 deletion causes reduced ILC3 numbers,increasing susceptibility to C.rodentium infection.Mechanistically,circZbtb20 enhances the interaction of Alkbh5 with Nr4a1 mRNA,leading to ablation of the m6A modification of Nr4a1 mRNA to promote its stability.Nr4a1 initiates Notch2 signaling activation,which contributes to the maintenance of ILC3 homeostasis.Deletion of Alkbh5 or Nr4a1 also impairs ILC3 homeostasis and increases susceptibilities to bacterial infection.Thus,our findings reveal an important role of circular RNA in the regulation of innate lymphoid cell homeostasis.

Regulation of noncoding RNAs in innate lymphoid cells

Innate lymphoid cells(ILCs)have been defined in recent years and are important effector cells against pathogens and critical regulators in maintaining tissue homeostasis[1].Noncoding RNAs(ncRNAs),such as circular RNAs(circRNAs),long noncoding RNAs(lncRNAs),and microRNAs(miRNAs),in ILCs are emerging and have been described to function in ILC biology.These ncRNAs are distributed with unique patterns in ILCs and function in different molecular mechanisms.Accumulating research evidence demonstrates that ncRNA dysregulation links ILC-mediated immune responses and diseases.

Induction of functional neutrophils from mouse fibroblasts by thymidine through enhancement of Tet3 activity

Neutrophils are derived from bone marrow hematopoietic stem cells(HSCs)and are the largest population among circulating white blood cells in humans,acting as the first line of defense against invading pathogens.Whether neutrophils can be generated by transdifferentiation strategies is unknown.Here,we show that thymidine induces the conversion of mouse fibroblasts to neutrophils.Induced neutrophils(iNeus)showed antibacterial effects and did not undergo malignant transformation in vivo.Importantly,iNeu transplantation cured neutropenia in mice in vivo.Mechanistically,thymidine mediates iNeu conversion by enhancing Tet3 activity.Tet3 initiates the expression of the neutrophil fate decision factors Cebpδ and Rfx1 that drive the transdifferentiation of mouse fibroblasts to neutrophils.Therefore,the induction of functional neutrophils by chemicals may provide a potential therapeutic strategy for patients with neutropenia patients and infectious diseases.

E）NA sensor cGAS-mediated immune recognition

The host takes use of pattern recognition receptors （PRRs） to defend against pathogen invasion or cellular damage. Among microorganism-associated molecular patterns detected by host PRRs, nucleic acids derived from bacteria or viruses are tightly supervised, providing a fundamental mechanism of host defense. Pathogenic DNAs are supposed to be detected by DNA sensors that induce the activation of NFKB or TBKI-IRF3 pathway. DNA sensor cGAS is widely expressed in innate immune cells and is a key sensor of invading DNAs in several cell types, cGAS binds to DNA, followed by a conformational change that allows the synthesis of cyclic guanosine monophosphate-adenosine monophosphate （cGAMP） from adenosine triphosphate and guanosine triphos- phate, cGAMP is a strong activator of STING that can activate IRF3 and subsequent type I interferon produc- tion. Here we describe recent progresses in DNA sensors especially cGAS in the innate immune responses against pathogenic DNAs.

LRRK2 enhances Nod1/2-mediated inflammatory cytokine production by promoting Rip2 phosphorylation

The innate immune system is critical for clearing infection, and is tightly regulated to avert excessive tissue damage. Nod1/2-Rip2 signaling, which is essential for initiating the innate immune response to bacterial infection and ER stress, is subject to many regulatory mechanisms. In this study, we found that LRRK2, encoded by a gene implicated in Crohn＇s disease, leprosy and familial Parkinson＇s disease, modulates the strength of Nod1/2-Rip2 signaling by enhancing Rip2 phosphorylation. LRRK2 deficiency markedly reduces cytokine production in macrophages upon Nod2 activation by muramyl dipeptide （MDP）, Nod1 activation by D-gamma-Glu-meso-diaminopimelic acid （iE-DAP） or ER stress. Our biochemical study shows that the presence of LRRK2 is necessary for optimal phosphorylation of Rip2 upon NOd2 activation. Therefore, this study reveals that LRRK2 is a new positive regulator of Rip2 and promotes inflammatory cytokine induction through the Nod1/2-Rip2 pathway.

Multimodal Studies in Hepatitis B Virus Associated Hepatocellular Carcinoma

Hepatocellular carcinoma(HCC)is a highly aggressive cancer that ranks the second leading cause of cancer related death.Hepatitis B virus(HBV)infection is the most prevalent etiological factor,especially in eastern world.However,the underlying mechanism of HBV infection-initialed carcinogenic progression remains largely unknown,making it difficult to improve therapeutic strategies for HBV-associated HCC(HBV+HCC).The virus drives multi-omics changes in human liver cells,leading to genomic in stability,epigenomic modifications,and proteomic a lterations.HBV infection also orchestrates the immunosuppressive microenv ironment in HBV+HCC.This review summarized recent research progress with the multimodal methods covering genome,transcriptome,epigenome,and proteome introduced in the mechanistic studies for HBV+HCC.