SARS-CoV-2-Encoded MiRNAs Inhibit Host Type I Interferon Pathway and Mediate Allelic Differential Expression of Susceptible Gene

Infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the rapid spread of coronavirus disease 2019 (COVID-19), has generated a public health crisis worldwide. The molecular mechanisms of SARS-CoV-2 infection and virus–host interactions are still unclear. In this study, we identified four unique microRNA-like small RNAs encoded by SARS-CoV-2. SCV2-miR-ORF1ab-1-3p and SCV2-miR-ORF1ab-2-5p play an important role in evasion of type I interferon response through targeting several genes in type I interferon signaling pathway. Particularly worth mentioning is that highly expressed SCV2-miR-ORF1ab-2-5p inhibits some key genes in the host innate immune response, such as IRF7, IRF9, STAT2, OAS1, and OAS2. SCV2-miR-ORF1ab-2-5p has also been found to mediate allelic differential expression of COVID-19-susceptible gene OAS1. In conclusion, these results suggest that SARS-CoV-2 uses its miRNAs to evade the type I interferon response and links the functional viral sequence to the susceptible genetic background of the host.

Nematode RALF-Like 1 Targets Soybean Malectin-Like Receptor Kinase to Facilitate Parasitism

Soybean [Glycine max (L.) Merr. ] is one of the most strategical oilseed crops that provides sustainable source of protein and oil worldwide. Cultivation of soybean is severely affected by root-knot nematode (RKN). However, the mechanism of RKN parasitism to soybeans is largely unknown. In this study, we identify GmLMM1, which encodes a homolog of FERONIA-like receptor kinase in soybean, as a susceptible gene toward nematode. Mutations of GmLMM1 exhibit enhanced resistance against the RKN Meloidogyne incognita. RNA-sequencing (RNA-seq) analysis reveals a similar differential expression pattern for genes regulated by GmLMM1 (Gmlmm1 vs. wild-type) and M. incognita (M. incognita vs. mock), supporting the role of GmLMM1 in M. incognita infection. Unlike FERONIA in Arabidopsis, GmLMM1 specifically binds to MiRALF1 and AtRALF23 that suppress plant immunity, but not MiRALF3 and AtRALF1. Moreover, we found that the single-nucleotide polymorphism (SNP) in GmLMM1 leads to the natural resistance against RKNs in soybeans. Collectively, these findings uncover GmLMM1 as a susceptible target of nematode RALF-like 1 and provide new genetic resource for nematode resistant breeding.

Genome-wide Identification, Characterization, and Function Analysis Uncovered Roles of Wheat TaLIM in Responding to Adverse Stress and TaLIM8-4D Function as a Susceptible Gene

Background: The LIM (Lin-11, Isl-1 and Mec-3 domains) transcription factors play essential roles in regulating plant biological processes, including cytoskeletal organization, development of secondary cell wall, and cell differentiation. Despite their important roles, there lacks a fully understanding of LIMs in wheat.Results: In this study, 28 TaLIMs (Triticum aestivum LIM) were identified and designated as TaLIM1-1A to TaLIM12-7D. Phylogenetic relationship analysis showed that TaLIMs could be divided into two groups (Group Ⅰ and Group Ⅱ), and the exon/intron structure analysis suggested that members in the same group have similar gene structure. Chromosome mapping showed that 28 TaLIMs were unevenly distributed on 18 chromosomes. Motif analysis revealed that 28 TaLIMs contained 15 motifs, of which motif1 (LIM-domain) was detected in all TaLIMs. Protein characterization indicated that TaLIMs were hydrophilic proteins and most of them were unstable. They were mainly comprised by α-helix and β-turn and without signal peptides. Duplication, Ka/Ks, and synthesis analyses suggested that polyploidization played fundamental role in the expansion of TaLIM members. Function annotations indicated that all TaLIMs were annotated under GO terms “zinc ion binding” (GO:0008270). The cis-regulatory element analysis showed that TaLIMs were rich in elements related to biological/abiotic stress, growth and development, and phytohormone response. RNA-seq data analysis showed certain members of TaLIMs were responsive to biotic and/or abiotic stresses. Such as TaLIM1-1A, TaLIM3-2B, TaLIM8-4D, and TaLIM10-5D were significantly induced by heat, drought, NaCl, ABA and Fusarium graminearum stresses. The subcellular localization of TaLIM8-4D show that it was in the nucleus. Furthermore, the biological function of TaLIM8-4D was analyzed and results showed that it could induce weak cell death in Nicotiana benthamiana leaf. Besides, overexpression of TaLIM8-4D could up-regulate plant pathogenesis-related (PR) genes, whereas promoted the infection of hemi-biotrophic pathogen, implying that TaLIM8-4D could function as susceptible gene in nucleus by up-regulating PR genes and inducing cell death to promote the colonization of hemi-biotrophic agent F. graminearum.Conclusion: The systematic identification, characterization, expression profiling, evolutionary, and function analyses provided us the fully understanding to TaLIMs and laid a foundation for the further function study of LIM family members in wheat.

The Candidate Schizophrenia Risk Gene Tmem108 Regulates Glucose Metabolism Homeostasis

BackgroundSchizophrenia (SCZ) is a severe psychiatric disease affected by genetic factors and environmental contributors, and premorbid abnormality of glucose metabolism is one of the SCZ characteristics supposed to contribute to the disease’s pathological process. Transmembrane protein 108 (Tmem108) is a susceptible gene associated with multiple psychiatric diseases, including SCZ. Moreover, Tmem108 mutant mice exhibit SCZ-like behaviors in the measurement of sensorimotor gating. However, it is unknown whether Tmem108 regulates glucose metabolism homeostasis while it involves SCZ pathophysiological process.ResultsIn this research, we found that Tmem108 mutant mice exhibited glucose intolerance, insulin resistance, and disturbed metabolic homeostasis. Food and oxygen consumption decreased, and urine production increased, accompanied by weak fatigue resistance in the mutant mice. Simultaneously, the glucose metabolic pathway was enhanced, and lipid metabolism decreased in the mutant mice, consistent with the elevated respiratory exchange ratio (RER). Furthermore, metformin attenuated plasma glucose levels and improved sensorimotor gating in Tmem108 mutant mice.ConclusionsHyperglycemia occurs more often in SCZ patients than in control, implying that these two diseases share common biological mechanisms, here we demonstrate that the Tmem108 mutant may represent such a comorbid mechanism.

Multi-Scale Understanding of NMDA Receptor Function in Schizophrenia

Schizophrenia is a chronic and disabling psychiatric disorder characterized by disturbances of thought, cognition, and behavior. Despite massive research efforts to date, the etiology and pathophysiology of schizophrenia remain largely unknown. The difficulty of brain research is largely a result of complex interactions between contributory factors at different scales: susceptible gene variants (molecular scale), synaptopathies (synaptic, dendritic, and cell scales), and alterations in neuronal circuits (circuit scale), which together result in behavioral manifestations (individual scale). It is likely that each scale affects the others, from the microscale to the mesoscale to the macroscale, and vice versa. Thus, to consider the intricate complexity of schizophrenia across multiple layers, we introduce a multi-scale, hierarchical view of the nature of this disorder, focusing especially on N-methyl-D-aspartate-type glutamate receptors (NMDARs). The reason for placing emphasis on NMDAR is its clinical relevance to schizophrenia, as well as its diverse functions in neurons, including the robust supralinear synaptic integration provided by N-methyl-D-aspartate-type glutamate (NMDA) spikes and the Ca2+ permeability of the NMDAR, which facilitates synaptic plasticity via various calcium-dependent proteins. Here, we review recent evidence implicating NMDARs in the pathophysiology of schizophrenia from the multi-scale perspective. We also discuss recent advances from optical techniques, which provide a powerful tool for uncovering the mechanisms of NMDAR synaptic pathology and their relationships, with subsequent behavioral manifestations.

Aryl Hydrocarbon Receptor Activation Downregulates IL-33 Expression in Keratinocytes via Ovo-Like 1

Background: IL-33, one of the IL-1 superfamily cytokines, has been shown to be associated with pruritus and inflammation in atopic dermatitis (AD). Furthermore, IL-33 production derived from keratinocytes reportedly has a crucial role in the development of AD; however, the mechanism of IL-33 expression has not been fully understood. Methods: We analyzed IL-33 expression in normal human epidermal keratinocytes (NHEKs) treated with IL-4. Results: IL-4 induced the upregulation of IL-33 expression in NHEKs. Based on the findings 1) that ovo-like 1 (OVOL1), a susceptible gene of AD, upregulates filaggrin (FLG) and loricrin (LOR) expression in NHEKs and 2) that reduced expression of FLG and LOR leads to production of IL-1 superfamily cytokines, we examined the involvement of OVOL1 in IL-33 expression in NHEKs. Knockdown of OVOL1 induced upregulation of IL-33 expression. Moreover, because Glyteer, an activator of aryl hydrocarbon receptor (AHR), reportedly upregulates OVOL1 expression, we examined whether treatment with Glyteer inhibited IL-33 expression in NHEKs. Treatment with Glyteer inhibited IL-4-induced upregulation of IL-33 expression, which was canceled by knockdown of either AHR or OVOL1. Conclusions: Activation of the AHR-OVOL1 axis inhibits IL-4-induced IL-33 expression, which could be beneficial for the treatment of AD.